Total submissions: 78
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV004566711 | SCV004101432 | pathogenic | BRCA2-related cancer predisposition | 2024-06-11 | reviewed by expert panel | curation | The c.5946del variant in BRCA2 is a deletion of a single nucleotide, predicted to encode a frameshift with consequent premature termination of the protein at codon 22 of the frameshift, or amino acid 2003 (p.Ser1982ArgfsTer22). This deletion variant was not observed in gnomAD v2.1 (exomes only, non-cancer subset) or gnomAD v3.1 (non-cancer subset), but PM2_Supporting was not applied since recall is suboptimal for this type of variant (PM2_Supporting not met). Frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 11 leading to nonsense mediated decay (PVS1 met). The ENIGMA BRCA1/2 VCEP considered multiple lines of functional and clinical evidence to define exon-specific weights for PTC in BRCA2, and results indicate that strong evidence towards pathogenicity may be applied for a PTC variant in BRCA2 exon 11 (PM5_Strong (PTC)). This variant has been detected in 6 individuals with phenotype consistent with BRCA2-Fanconi Anemia (FA). At least two clinical features of FA (physical features, pathology findings and cancer diagnosis <=5yr) and confirmed chromosome breakage, are seen in these individuals. 6 were compound heterozygous for the variant and a pathogenic or likely pathogenic variant, and confirmed to be in trans. Total points equated to 8 (PM3_Strong met; PMIDs: 14559878, 15516848, 16825431, 19530235). In summary, this variant meets the criteria to be classified as a Pathogenic variant for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PVS1, PM5_Strong (PTC), PM3_Strong). |
| Labcorp Genetics |
RCV000034451 | SCV000072813 | pathogenic | Hereditary breast ovarian cancer syndrome | 2025-02-03 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Ser1982Argfs*22) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). This variant is present in population databases (rs80359550, gnomAD 0.6%). This premature translational stop signal has been observed in individual(s) with breast (43% to 55% lifetime risk) and/or ovarian cancer (20% to 37% lifetime risk) (PMID: 8758903, 9042909, 10417300, 15994883, 22430266). It is commonly reported in individuals of Ashkenazi Jewish ancestry (PMID: 8758903, 9042909, 10417300, 22430266). This premature translational stop signal has been observed to co-occur in individuals with a different variant in BRCA2 that has been determined to be pathogenic (internal data), but the significance of this finding is unclear. This variant is also known as 6174delT. ClinVar contains an entry for this variant (Variation ID: 9325). For these reasons, this variant has been classified as Pathogenic. |
| Gene |
RCV000212245 | SCV000108631 | pathogenic | not provided | 2020-06-11 | criteria provided, single submitter | clinical testing | Common founder variant in the Ashkenazi Jewish population (Oddoux 1996); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate a damaging effect: increased sensitivity to MMC, decreased HDR, and increased centrosome amplification compared to wild-type (Wu 2005); Observed in approximately 1% of the Ashkenazi Jewish population (Oddoux 1996); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 6174delT; This variant is associated with the following publications: (PMID: 20736950, 20887823, 28049106, 28291774, 30620386, 27836010, 23633455, 15695382, 19188187, 22703879, 22009639, 22430266, 23658460, 23341105, 22006311, 21324516, 8673091, 25980754, 26440929, 27425403, 14559878, 26681312, 29321669, 29339979, 29433453, 29368341, 29084914, 27989354, 29907814, 26556299, 10464624, 28767289, 8841192, 29161300, 29439820, 30274973, 30152102, 29506128, 30122538, 30716324, 30186769, 30720243, 29961768, 30702160, 29978187, 30322717, 29937315, 30113427, 30489631, 31263054, 31444830, 32438681, 31512090, 29625052, 26689913, 31447099, 31948886, 34308366, 10739756, 10733239, 34399810, 33077847, 31589614, 32853339, 32341426, 32719484, 32885271, 32338768, 30787465, 30613976, 33087929) |
| Counsyl | RCV000009910 | SCV000154098 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 2 | 2014-04-07 | criteria provided, single submitter | literature only | |
| Ambry Genetics | RCV000129627 | SCV000184420 | pathogenic | Hereditary cancer-predisposing syndrome | 2025-02-24 | criteria provided, single submitter | clinical testing | The c.5946delT (p.S1982Rfs*22) alteration, located in exon 11 (coding exon 10) of the BRCA2 gene, consists of a deletion of one nucleotide at position 5946, causing a translational frameshift with a predicted alternate stop codon after 22 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, this allele has an overall frequency of 0.028% (78/282088) total alleles studied. The highest observed frequency was 0.589% (61/10364) of Ashkenazi Jewish alleles. This variant is one of the well-described Ashkenazi Jewish founder mutations and has been reported in numerous families affected with breast, ovarian, prostate, pancreatic, and other HBOC-related cancers (Agalliu, 2009; Walsh, 2011; Johnston, 2012; Bayraktar, 2012; George, 2013; Lucas, 2013; Salo-Mullen, 2015; Susswein, 2016). This variant has also been reported in trans with a second variant in individuals affected with Fanconi anemia (Offit, 2003; Dewire, 2009). One study indicated that carriers of the c.5946delT mutation may have a lower relative risk for breast cancer when compared to carriers of other non-Ashkenazi Jewish BRCA2 mutations (Finkelman, 2012); however, other studies have reported the overall risk as similar to that of other pathogenic mutations in the ovarian cancer cluster region (OCCR) of coding exon 10 of BRCA2 (Kuchenbaecker, 2017). This variant is also designated as 6174delT in published literature. Based on the available evidence, this alteration is classified as pathogenic. |
| Michigan Medical Genetics Laboratories, |
RCV000009910 | SCV000195993 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 2 | 2014-11-03 | criteria provided, single submitter | clinical testing | |
| CHEO Genetics Diagnostic Laboratory, |
RCV000768632 | SCV000219371 | pathogenic | Breast and/or ovarian cancer | 2022-03-06 | criteria provided, single submitter | clinical testing | |
| Eurofins Ntd Llc |
RCV000212245 | SCV000225181 | pathogenic | not provided | 2017-02-03 | criteria provided, single submitter | clinical testing | |
| Color Diagnostics, |
RCV000129627 | SCV000292121 | pathogenic | Hereditary cancer-predisposing syndrome | 2023-03-06 | criteria provided, single submitter | clinical testing | This variant deletes 1 nucleotide in exon 11 of the BRCA2 gene, causing a frameshift and a premature translational stop signal. This variant is also known as 6174delT in the literature. This variant is expected to result in an absent or non-functional protein product. Functional studies have reported that this variant impacts BRCA2 function in homology-directed repair and other ancillary assays (PMID: 15695382, 18607349). This variant is a well-known founder mutation in the Ashkenazi Jewish population and occurs at 0.6-1.52% minor allele frequency (PMID: 8673092, 30152102). This variant has been reported in dozens of individuals affected with breast and/or ovarian cancer in Ashkenazi Jewish and in non-Ashkenazi Jewish populations (PMID: 8524414, 8673091, 8673092, 8758903, 8898735, 8841191, 9145676, 12473589, 14576434, 20104584, 21324516, 22006311, 22430266, 28944232, 29084914, 29433453). This variant has been reported with cosegregation likelihood ratio for pathogenicity of over 1,000 (PMID: 15695382) and in a breast cancer case-control meta-analysis in 26/60440 cases and 8/53453 unaffected individuals with OR 2.874 (95%CI 1.301 to 6.349) (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_000149). The risk of female breast cancer among carriers of this mutation is 43-55% by age 70, and the risk of ovarian cancer is 18-37% by age 70 (PMID: 9145676, 15994883, 22430266). This variant has been identified in 78/282088 chromosomes in the general population (61/10364 Ashkenazi Jewish chromosomes) by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. |
| Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000212245 | SCV000296747 | pathogenic | not provided | 2021-08-19 | criteria provided, single submitter | clinical testing | This frameshift variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. The frequency of this variant in the general population, 0.00011 (14/128890 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported as a BRCA2 founder variant in the Ashkenazi Jewish population with a carrier frequency of approximately 1.52% (PMID: 17591843 (2007) and 8841191 (1996)). Based on the available information, this variant is classified as pathogenic. |
| Consortium of Investigators of Modifiers of BRCA1/2 |
RCV000009910 | SCV000327312 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 2 | 2015-10-02 | criteria provided, single submitter | clinical testing | |
| Illumina Laboratory Services, |
RCV000367838 | SCV000383728 | pathogenic | BRCA2-related disorder | 2017-04-28 | criteria provided, single submitter | clinical testing | The BRCA2 c.5946delT (p.Ser1982ArgfsTer22) variant, more commonly known as c.6174delT, results in a frameshift and premature termination of the protein. The p.Ser1982ArgfsTer22 variant is a well-described founder variant in the BRCA2 gene that is prevalent in the Ashkenazi Jewish and Icelandic populations, with a carrier frequency of ~1.5% (Roa et al. 1996; Neuhausen et al. 1996). The variant has been shown to occur in approximately eight percent of women diagnosed with breast cancer before the age of 42 years (Neuhausen et al. 1996; Oddoux et al. 1996; Petrucelli et al. 2010; Finkelman et al. 2012). By the age of 70, 43% of individuals who carry this variant are predicted to develop breast cancer and 20% are predicted to develop ovarian cancer (Struewing et al. 1997; King et al. 2003). Across a selection of the literature, the p.Ser1982ArgfsTer22 variant has been identified in 55 of 1,272 (4%) individuals with breast cancer, 44 of 382 (11.5%) individuals with ovarian cancer, and at least 118 of 9,658 (1.2%) Ashkenazi Jewish individuals from the general population (Couch et al. 1996; Roa et al. 1996; Neuhausen et al. 1996; Oddoux et al. 1996; Struewing et al. 1997; Satagopan et al. 2002; King et al. 2003). Additionally, the p.Ser1982ArgfsTer22 variant has been identified in a compound heterozygous state in four individuals, including two cousins, with Fanconi anemia and brain tumors from three different Ashkenazi Jewish families (Offit et al. 2003; Alter et al. 2007). The p.Ser1982ArgfsTer22 variant was absent from at least 1,726 non-Ashkenazi Jewish controls and is reported at a frequency of 0.00048 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies demonstrated decreased cell viability and survival in carriers of the p.Ser1982ArgfsTer22 variant (Wu et al. 2005). The variant protein was shown to be localized in the cytoplasm and not in the nucleus. The p.Ser1982ArgfsTer22 variant is predicted to result in truncation of approximately 41% of the BRCA2 protein, which would remove two signals required for nuclear localization and represents a likely mode of pathogenicity for the variant (Spain et al. 1999). In a study in mouse embryonic stem cells, the p.Ser1982ArgfsTer22 variant failed to rescue the loss of endogenous BRCA2 (Kuznetsov et al. 2008). Based on the collective evidence, the p.Ser1982ArgfsTer22 variant is classified as pathogenic for BRCA2-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. |
| A. |
RCV000414179 | SCV000492446 | pathogenic | Breast neoplasm | criteria provided, single submitter | research | ||
| Baylor Genetics | RCV000044800 | SCV000540997 | pathogenic | Familial cancer of breast | 2024-03-29 | criteria provided, single submitter | clinical testing | |
| Fulgent Genetics, |
RCV000009910 | SCV000575747 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 2 | 2016-02-12 | criteria provided, single submitter | clinical testing | |
| Genetic Services Laboratory, |
RCV000009910 | SCV000593749 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 2 | 2016-05-16 | criteria provided, single submitter | clinical testing | |
| ARUP Laboratories, |
RCV000212245 | SCV000602754 | pathogenic | not provided | 2024-10-25 | criteria provided, single submitter | clinical testing | The BRCA2 c.5946delT; p.Ser1982ArgfsTer22 variant (rs80359550), also published as 6174delT, is reported as a pathogenic founder variant in the Ashkenazi Jewish population (Abeliovich 1997, Couch 1996, Finkelman 2012), and has been associated with hereditary breast and ovarian cancer syndrome. The variant is reported as pathogenic by several sources in the ClinVar database (Variation ID: 9325) and is found in the Ashkenazi Jewish population with an allele frequency of 0.6% (61/10,364 alleles) in the Genome Aggregation Database. This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Abeliovich D et al. The founder mutations 185delAG and 5382insC in BRCA1 and 6174delT in BRCA2 appear in 60% of ovarian cancer and 30% of early-onset breast cancer patients among Ashkenazi women. Am J Hum Genet. 1997 Mar;60(3):505-14. PMID: 9042909. Couch FJ et al. BRCA2 germline mutations in male breast cancer cases and breast cancer families. Nat Genet. 1996 May;13(1):123-5. PMID: 8673091. Finkelman BS et al. Breast and ovarian cancer risk and risk reduction in Jewish BRCA1/2 mutation carriers. J Clin Oncol. 2012 Apr 20;30(12):1321-8. PMID: 22430266. |
| Department of Medical Genetics, |
RCV000009910 | SCV000605651 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 2 | 2015-07-01 | criteria provided, single submitter | clinical testing | |
| Laboratory for Molecular Medicine, |
RCV000034451 | SCV000605785 | pathogenic | Hereditary breast ovarian cancer syndrome | 2023-06-07 | criteria provided, single submitter | clinical testing | The p.Ser1982ArgfsX22 variant in BRCA2 is a founder mutation in the Ashkenazi Jewish population (Finkelman 2012 PMID: 22430266) and has been identified in >500 individuals of various ethnicities with BRCA2-associated cancers (Breast Cancer Information Core (BIC) database: https://research.nhgri.nih.gov/projects/bic/). It has also been identified in 0.6% (20/3466) of Ashkenazi Jewish and 0.009% (6/68002) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1982 and leads to a premature termination codon 22 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function BRCA2 is an established disease mechanism for hereditary breast and ovarian cancer (HBOC) syndrome. Additionally, this variant was classified as pathogenic on April 22, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar variation ID 9325). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PS4_Strong. |
| Institute for Biomarker Research, |
RCV000129627 | SCV000679720 | pathogenic | Hereditary cancer-predisposing syndrome | 2017-07-12 | criteria provided, single submitter | clinical testing | |
| Gene |
RCV000212245 | SCV000693574 | pathogenic | not provided | 2020-01-01 | criteria provided, single submitter | clinical testing | This variant is a deletion of one nucleotide, resulting in a frameshift and the creation of a novel translational stop codon after 22 amino acid residues. The protein product thus produced is truncated and non-functional. Truncating variants in BRCA2 are known to be pathogenic. In the literature, this variant is also known as 6174delT and is a common cause of breast and ovarian cancer in the Ashkenazi Jewish population (PMID: 9042909, 22430266). Moreover, it has been reported in individuals of other ethnicities (PMID: 8758903, 10417300). This variant has been associated with a 43% to 55% risk of breast cancer by age 70, and a 20% to 37% risk of ovarian cancer by age 70 (PMID: 15994883). The mutation database ClinVar contains entries for this variant (Variation ID: 9325). |
| Clinical Genetics DNA and cytogenetics Diagnostics Lab, |
RCV000009910 | SCV000744479 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 2 | 2015-09-21 | criteria provided, single submitter | clinical testing | |
| Mayo Clinic Laboratories, |
RCV000212245 | SCV000778694 | pathogenic | not provided | 2024-07-25 | criteria provided, single submitter | clinical testing | PM3_strong, PM5_strong, PVS1 |
| Equipe Genetique des Anomalies du Developpement, |
RCV000009910 | SCV000803796 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 2 | 2017-11-07 | criteria provided, single submitter | clinical testing | |
| Gharavi Laboratory, |
RCV000212245 | SCV000809465 | pathogenic | not provided | 2018-09-16 | criteria provided, single submitter | research | |
| Mendelics | RCV000034451 | SCV000838826 | pathogenic | Hereditary breast ovarian cancer syndrome | 2018-07-02 | criteria provided, single submitter | clinical testing | |
| Human Genome Sequencing Center Clinical Lab, |
RCV000009910 | SCV000839905 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 2 | 2017-05-24 | criteria provided, single submitter | clinical testing | The c.5946del (p.Ser1982Argfs*22) variant has been detected in a multiple patients with breast and ovarian cancer [reported as c.6174del in PMID 8673091, 23633455, 22006311, 21324516, 22430266]. The variant was also detected in patients with prostate cancer [PMID 19188187, 20736950] and pancreatic ductal adenocarcinoma [PMID 23658460]. This variant is associated with a cancer risk of 50-43% and 18-20% risk for breast and ovarian cancer respectively by age 70 [PMID 9145676,15994883]. In vitro assays showed that this variant leads to a loss of function of the protein [PMID 15695382]. This variant has been reported in 32 non-Finnish Europeans from the ExAC database (http://exac.broadinstitute.org/variant/13-32914437-GT-G). This c.5946del (p.Ser1982Argfs*22) variant occurs at high frequency in the Ashkenazi Jewish population and is considered a founder mutation in this population. This variant is thus classified as pathogenic.[leduc, 2017-03-07] |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000034451 | SCV000918979 | pathogenic | Hereditary breast ovarian cancer syndrome | 2019-05-01 | criteria provided, single submitter | clinical testing | Variant summary: BRCA2 c.5946delT (p.Ser1982ArgfsX22) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.0002765 in 282088 control chromosomes (gnomAD), which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503) and was predominantly observed in the Ashkenazi Jewish subpopulation. This variant is a well-established Ashkenazi Jewish founder mutation. The variant, c.5946delT, has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (Abeliovich_1997, Friedman_1998). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Wu_2005). Multiple ClinVar submissions after 2014 cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
| Rady Children's Institute for Genomic Medicine, |
RCV000129627 | SCV000996186 | pathogenic | Hereditary cancer-predisposing syndrome | 2018-08-14 | criteria provided, single submitter | clinical testing | This variant is also known as c.6174delT using alternate nomenclature. This variant is known as a founder mutation in the Ashkenazi Jewish population (PMID: 20301425) and has been previously reported as a heterozygous change in multiple individuals with a personal or family history of breast and/or ovarian cancer, among other types of cancer (PMID: 20301425, 29084914, 29433453, 2644092, 29321669, 28767289). Based on the available evidence, the c.5946delT (p.Ser1982ArgfsTer22) variant is classified as pathogenic. |
| Clinical Genetics and Genomics, |
RCV000212245 | SCV001450241 | pathogenic | not provided | 2014-08-07 | criteria provided, single submitter | clinical testing | |
| Department of Pediatrics, |
RCV000009910 | SCV001478111 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 2 | 2020-12-15 | criteria provided, single submitter | research | |
| Ce |
RCV000212245 | SCV001501475 | pathogenic | not provided | 2025-02-01 | criteria provided, single submitter | clinical testing | BRCA2: PVS1, PS4:Moderate, PM2:Supporting |
| Institute of Medical Genetics and Applied Genomics, |
RCV000212245 | SCV001762173 | pathogenic | not provided | 2021-06-17 | criteria provided, single submitter | clinical testing | |
| Institute of Human Genetics, |
RCV000009910 | SCV001934380 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 2 | 2021-01-04 | criteria provided, single submitter | clinical testing | |
| Institute for Clinical Genetics, |
RCV000212245 | SCV002010347 | pathogenic | not provided | 2021-11-03 | criteria provided, single submitter | clinical testing | |
| Revvity Omics, |
RCV000212245 | SCV002019064 | pathogenic | not provided | 2023-11-16 | criteria provided, single submitter | clinical testing | |
| National Health Laboratory Service, |
RCV000034451 | SCV002025788 | pathogenic | Hereditary breast ovarian cancer syndrome | 2021-11-16 | criteria provided, single submitter | clinical testing | |
| St. |
RCV000034451 | SCV002526014 | pathogenic | Hereditary breast ovarian cancer syndrome | 2022-03-22 | criteria provided, single submitter | clinical testing | The BRCA2 c.5946del (p.Ser1982ArgfsTer22) change causes a frameshift and the creation of a premature stop codon. This change is predicted to cause protein truncation or absence of the protein due to nonsense mediated decay (PVS1). This variant has a maximum subpopulation frequency of 0.59% in gnomAD v2.1.1, where it is primarily found in the Ashkenazi Jewish population (https://gnomad.broadinstitute.org/variant/13-32914437-GT-G?dataset=gnomad_r2_1). This variant has been reported in multiple individuals with breast cancer and/or ovarian cancer (PMID: 8673092, 9042909, 9150153, 15994883, 22430266, 30152102). It is a well-established pathogenic founder variant in the Ashkenazi Jewish population (PMID: 9042909, 22430266). This alteration is also known as 6174delT in the literature. In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria: PVS1, PS4. |
| Sema4, |
RCV000129627 | SCV002536189 | pathogenic | Hereditary cancer-predisposing syndrome | 2021-10-23 | criteria provided, single submitter | curation | |
| Center for Genomic Medicine, |
RCV000212245 | SCV002550357 | pathogenic | not provided | 2025-03-04 | criteria provided, single submitter | clinical testing | |
| Johns Hopkins Genomics, |
RCV000009910 | SCV002570374 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 2 | 2022-05-03 | criteria provided, single submitter | clinical testing | This variant (rs28897738) has been reported in the literature in association with a variety of BRCA2-related cancer conditions that are inherited in a dominant or recessive manner. It is known as a founder mutation in the Ashkenazi Jewish population and has also been observed in individuals of non-Ashkenazi Jewish descent. It is rare (<0.1%) in a large population dataset (gnomAD: 78/282088 total alleles; 0.0277%; no homozygotes) and has been reported in ClinVar(Variation ID 9325). This frameshift variant results in a premature stop codon in exon 11, likely leading to nonsense-mediated decay and lack of protein production and has supporting functional evidence. We consider this variant to be pathogenic. |
| MGZ Medical Genetics Center | RCV000009910 | SCV002581177 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 2 | 2022-08-02 | criteria provided, single submitter | clinical testing | |
| Genetics and Molecular Pathology, |
RCV000009910 | SCV002761748 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 2 | 2020-04-17 | criteria provided, single submitter | clinical testing | |
| New York Genome Center | RCV000009910 | SCV002764549 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 2 | 2022-03-31 | criteria provided, single submitter | clinical testing | The c.5946del, p.Ser1982ArgfsTer22 missense variant identified in BRCA2, also known as c.6174delT, results in a frameshift and premature termination of the protein. The p.Ser1982ArgfsTer22 variant is a founder variant in the BRCA2 gene that is prevalent in the Ashkenazi Jewish and Icelandic populations, and has been previously reported as a heterozygous change in multiple individuals with a personal or family history of breast and/or ovarian cancer, among other types of cancer (PMID: 20301425, 29084914, 29433453, 29321669, 28767289). Based on the available evidence, the c.5946delT, p.Ser1982ArgfsTer22 variant is classified as pathogenic. |
| Division Of Personalized Genomic Medicine, |
RCV000009910 | SCV004037369 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 2 | 2021-03-09 | criteria provided, single submitter | clinical testing | |
| Baylor Genetics | RCV000009910 | SCV004041350 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 2 | 2023-07-02 | criteria provided, single submitter | clinical testing | |
| Human Genetics Bochum, |
RCV000212245 | SCV004042779 | pathogenic | not provided | 2023-10-04 | criteria provided, single submitter | clinical testing | ACMG criteria used to clasify this variant:PVS1, PS4 |
| All of Us Research Program, |
RCV004566711 | SCV004846675 | pathogenic | BRCA2-related cancer predisposition | 2024-09-25 | criteria provided, single submitter | clinical testing | The c.5946del (p.Ser1982Argfs*22) variant has been detected in a multiple patients with breast and ovarian cancer [reported as c.6174del in PMID 8673091, 23633455, 22006311, 21324516, 22430266]. The variant was also detected in patients with prostate cancer [PMID 19188187, 20736950] and pancreatic ductal adenocarcinoma [PMID 23658460]. This variant is associated with a cancer risk of 50-43% and 18-20% risk for breast and ovarian cancer respectively by age 70 [PMID 9145676,15994883]. In vitro assays showed that this variant leads to a loss of function of the protein [PMID 15695382]. This variant has been reported in 32 non-Finnish Europeans from the ExAC database (http://exac.broadinstitute.org/variant/13-32914437-GT-G). This variant occurs at high frequency in the Ashkenazi Jewish population and is considered a founder mutation in this population. This variant is classified as pathogenic and considered medically actionable. [leduc, 2017-03-07] The c.5946del (p.Ser1982Argfs*22) variant has been detected in a multiple patients with breast and ovarian cancer [reported as c.6174del in PMID 8673091, 23633455, 22006311, 21324516, 22430266]. The variant was also detected in patients with prostate cancer [PMID 19188187, 20736950] and pancreatic ductal adenocarcinoma [PMID 23658460]. This variant is associated with a cancer risk of 50-43% and 18-20% risk for breast and ovarian cancer respectively by age 70 [PMID 9145676,15994883]. In vitro assays showed that this variant leads to a loss of function of the protein [PMID 15695382]. This variant has been reported in 32 non-Finnish Europeans from the ExAC database (http://exac.broadinstitute.org/variant/13-32914437-GT-G). This c.5946del (p.Ser1982Argfs*22) variant occurs at high frequency in the Ashkenazi Jewish population and is considered a founder mutation in this population. This variant is thus classified as pathogenic. |
| Department of Clinical Genetics, |
RCV000009910 | SCV005045989 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 2 | 2024-05-27 | criteria provided, single submitter | clinical testing | PM3_Strong; PVS1; PM5_PTC_Strong |
| Department of Human Genetics, |
RCV000009910 | SCV005073662 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 2 | 2024-07-04 | criteria provided, single submitter | clinical testing | |
| Clinical Genetics Laboratory, |
RCV000212245 | SCV005199797 | pathogenic | not provided | 2022-05-27 | criteria provided, single submitter | clinical testing | |
| Institute of Human Genetics, |
RCV000044800 | SCV005368163 | pathogenic | Familial cancer of breast | 2024-05-06 | criteria provided, single submitter | clinical testing | Criteria applied: PVS1,PM5_STR |
| Victorian Clinical Genetics Services, |
RCV000009910 | SCV005398704 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 2 | 2023-07-16 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with autosomal dominant BRCA2-related cancer and recessive fanconi anemia, complementation group D1 (MIM#605724). (I) 0108 - This gene is associated with both recessive and dominant disease. Predisposition to cancer follows an autosomal dominant inheritance pattern, while Fanconi anemia (MIM#605724) is associated with autosomal recessive inheritance (OMIM, PMID: 14559878). (I) 0112 - The condition associated with this gene has incomplete penetrance. Although Fanconi anemia (MIM#605724) is fully penetrant, the risk of malignancy in pathogenic variant carriers is not 100%; the highest risk estimates are for breast cancer at 38-84% (GeneReviews). The risk of breast and ovarian cancer for this variant specifically have been estimated at 43% and 20%, respectively (PMID: 15994883). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 (78 heterozygotes, 0 homozygotes). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic multiple times in the ClinVar database, and is curated as Pathogenic by the ENIGMA expert panel for familial breast and ovarian cancer (ClinVar). It has also been reported in the context of other cancers including prostate cancer and pancreatic adenocarcinoma (PMID: 19188187, 23658460). In a compound heterozygous state, this variant has been reported in individuals with Fanconi anaemia and brain tumours (PMID: 14559878, 16825431). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |
| Fulgent Genetics, |
RCV005007837 | SCV005633943 | pathogenic | Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 2; Fanconi anemia complementation group D1; Medulloblastoma; Wilms tumor 1; Pancreatic cancer, susceptibility to, 2; Glioma susceptibility 3; Familial prostate cancer | 2024-05-21 | criteria provided, single submitter | clinical testing | |
| OMIM | RCV000009910 | SCV000030127 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 2 | 1995-12-21 | no assertion criteria provided | literature only | |
| OMIM | RCV000009911 | SCV000030132 | risk factor | Pancreatic cancer, susceptibility to, 2 | 2016-09-12 | no assertion criteria provided | literature only | |
| OMIM | RCV000009912 | SCV000030133 | pathogenic | Fanconi anemia complementation group D1 | 2016-09-12 | no assertion criteria provided | literature only | |
| Biesecker Lab/Clinical Genomics Section, |
RCV000034451 | SCV000043218 | pathogenic | Hereditary breast ovarian cancer syndrome | 2012-07-13 | no assertion criteria provided | research | Converted during submission to Pathogenic. |
| Sharing Clinical Reports Project |
RCV000009910 | SCV000054198 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 2 | 2013-01-15 | no assertion criteria provided | clinical testing | |
| Gene |
RCV000034451 | SCV000086654 | not provided | Hereditary breast ovarian cancer syndrome | no assertion provided | literature only | Founder variant in Ashkenazi Jews; accounts for 95% of pathogenic variants in this population | |
| Breast Cancer Information Core |
RCV000009910 | SCV000146737 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 2 | 2002-05-29 | no assertion criteria provided | clinical testing | |
| Pathway Genomics | RCV000009910 | SCV000189906 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 2 | 2014-07-24 | no assertion criteria provided | clinical testing | |
| Curoverse | RCV000034451 | SCV000245334 | pathogenic | Hereditary breast ovarian cancer syndrome | 2015-08-01 | no assertion criteria provided | research | Frameshifts in BRCA2 are considered pathogenic, and this is a BRCA2 Ser1982Arg frameshift variant in exon 11 |
| Centro de Genética y Biología Molecular, |
RCV000009910 | SCV000263344 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 2 | 2015-06-10 | no assertion criteria provided | research | |
| Bioscientia Institut fuer Medizinische Diagnostik Gmb |
RCV000044800 | SCV000484936 | pathogenic | Familial cancer of breast | no assertion criteria provided | clinical testing | ||
| Research Molecular Genetics Laboratory, |
RCV000034451 | SCV000587812 | pathogenic | Hereditary breast ovarian cancer syndrome | 2014-01-31 | no assertion criteria provided | research | |
| Department of Pathology and Laboratory Medicine, |
RCV000009910 | SCV000592016 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 2 | no assertion criteria provided | clinical testing | The BRCA2 p.Ser1982Argfs*22 variant was identified in 33 of 11966 proband chromosomes (frequency: 0.003) from individuals or families with breast, ovarian and pancreatic cancer (Agalliu 2009, Borg 2010, Couch 2014, Edwards 2010, Zhang 2011). The variant was also identified in dbSNP (ID: rs80359550) as “With Pathogenic allele”, ClinVar (classified as pathogenic by 34 submitters including Invitae, GeneDx, Counsyl, ARUP and Ambry Genetics), COGR (3 entries classified as pathogenic), COSMIC (1x confirmed somatic in adenocarcinoma of the pancreas), LOVD 3.0 (110 entries classified as affects function), UMD-LSDB (75 entries classified as causal), BIC Database (1090 entries classified as pathogenic), ARUP Laboratories (classified as definitely pathogenic), and the Zhejiang Colon Cancer Database (classified as pathogenic). The variant was not identified in the MutDB database. The variant was also identified by our laboratory in multiple individuals with breast, ovarian or pancreatic cancer. The variant was identified in control databases in 72 of 276978 chromosomes at a frequency of 0.0003 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: Ashkenazi Jewish in 59 of 10150 chromosomes (freq: 0.006), Other in 3 of 6460 chromosomes (freq: 0.0005), European (Non-Finnish) in 10 of 126512 chromosomes (freq: 0.00008); it was not observed in the African, East Asian, European (Finnish), Latino, or South Asian populations. The c.5946delT variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1982 and leads to a premature stop codon 22 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the BRCA2 gene are an established mechanism of disease in hereditary breast and ovarian cancer and is the type of variant expected to cause the disorder. The truncating BRCA2 6174delT Ashkenazi Jewish founder mutation is associated with a breast cancer risk of 70% by age 70 and identified in the vast majority of Ashkenazi Jewish families with a history of breast and ovarian cancer (Pohlreich 2005, Wu 2005). In addition, a functional study using bacterial artificial chromosomes concluded that this mutation could not rescue lethality in BRCA2-deficient mouse embryonic stem cells, supporting its classification as deleterious (Kuznetsov 2008). In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. Assessment Date: 2018/03/07. | |
| Diagnostic Laboratory, |
RCV000009910 | SCV000733276 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 2 | no assertion criteria provided | clinical testing | ||
| True Health Diagnostics | RCV000129627 | SCV000787938 | pathogenic | Hereditary cancer-predisposing syndrome | 2017-09-27 | no assertion criteria provided | clinical testing | |
| Prevention |
RCV000367838 | SCV000805732 | pathogenic | BRCA2-related disorder | 2024-07-17 | no assertion criteria provided | clinical testing | The BRCA2 c.5946delT variant is predicted to result in a frameshift and premature protein termination (p.Ser1982Argfs*22). This variant, also described as 6174delT in the literature, has been associated with autosomal dominant hereditary breast and ovarian cancer syndrome (HBOC) (OMIM #612555; Couch et al. 1996. PubMed ID: 8673091). It has also been associated with autosomal recessive Fanconi anemia, complementation group D1 (OMIM #605724; Offit et al. 2003. PubMed ID: 14559878). This is a founder variant in the Ashkenazi Jewish population, identified in about 1.5% of Ashkenazi Jewish individuals unselected for breast cancer (Abeliovich et al. 1997. PubMed ID: 9042909; Roa et al. 1996. PubMed ID:8841191). This variant is frequently observed in the Ashkenazi Jewish population in gnomAD. This variant is also found in individuals of diverse ancestry at variable frequencies. It is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/9325/). In summary, this variant is interpreted as pathogenic. |
| German Consortium for Hereditary Breast and Ovarian Cancer, |
RCV000785226 | SCV000923794 | pathogenic | Ovarian neoplasm | 2018-12-01 | no assertion criteria provided | research | |
| Genome |
RCV001535431 | SCV001749320 | not provided | Fanconi anemia complementation group D1; Hereditary breast ovarian cancer syndrome | no assertion provided | phenotyping only | Variant reported in multiple Invitae PIN participants. Variant interpreted as Pathogenic and reported most recently on 7/5/2018 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. | |
| Laboratory of Diagnostic Genome Analysis, |
RCV000212245 | SCV001798609 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
| Clinical Genetics Laboratory, |
RCV000212245 | SCV001906091 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
| Genome Diagnostics Laboratory, |
RCV000212245 | SCV001926441 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
| Joint Genome Diagnostic Labs from Nijmegen and Maastricht, |
RCV000212245 | SCV002037347 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
| BRCAlab, |
RCV000009910 | SCV002588896 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 2 | 2022-08-26 | no assertion criteria provided | clinical testing | |
| CZECANCA consortium | RCV003128125 | SCV003804351 | pathogenic | Endometrial carcinoma | 2023-02-21 | no assertion criteria provided | clinical testing |