Total submissions: 46
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Evidence- |
RCV000009910 | SCV000282418 | pathogenic | Breast-ovarian cancer, familial 2 | 2016-04-22 | reviewed by expert panel | curation | Variant allele predicted to encode a truncated non-functional protein. |
Invitae | RCV000034451 | SCV000072813 | pathogenic | Hereditary breast and ovarian cancer syndrome | 2020-01-08 | criteria provided, single submitter | clinical testing | This sequence change deletes 1 nucleotide from exon 11 of the BRCA2 mRNA (c.5946delT), causing a frameshift at codon 1982. This creates a premature translational stop signal (p.Ser1982Argfs*22) and is expected to result in an absent or disrupted protein product. This pathogenic variant is a common cause of breast and ovarian cancer in the Ashkenazi Jewish population (PMID: 9042909, 22430266), and has been reported in individuals of other ethnicities (PMID: 8758903, 10417300). In the literature, this variant is also known as 6174delT. 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, 22430266). For these reasons, this variant has been classified as Pathogenic. |
Gene |
RCV000212245 | SCV000108631 | pathogenic | not provided | 2018-11-19 | criteria provided, single submitter | clinical testing | This pathogenic variant is denoted BRCA2 c.5946delT at the cDNA level and p.Ser1982ArgfsX22 (S1982RfsX22) at the protein level and is also known as 6174delT using alternate nomenclature. The normal sequence with the base that is deleted in brackets is CAAG[delT]GGAA. The deletion causes a frameshift, changing a Serine to an Arginine at codon 1982, and creating a premature stop codon at position 22 of the new reading frame. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. BRCA2 c.5946delT is known to be a pathogenic founder variant in the Ashkenazi Jewish population (Oddoux 1996). |
Counsyl | RCV000009910 | SCV000154098 | pathogenic | Breast-ovarian cancer, familial 2 | 2014-04-07 | criteria provided, single submitter | literature only | |
Ambry Genetics | RCV000129627 | SCV000184420 | pathogenic | Hereditary cancer-predisposing syndrome | 2018-09-20 | criteria provided, single submitter | clinical testing | Alterations resulting in premature truncation (e.g.reading frame shift, nonsense) |
Michigan Medical Genetics Laboratories, |
RCV000009910 | SCV000195993 | pathogenic | Breast-ovarian cancer, familial 2 | 2014-11-03 | criteria provided, single submitter | clinical testing | |
CHEO Genetics Diagnostic Laboratory, |
RCV000768632 | SCV000219371 | pathogenic | Breast and/or ovarian cancer | 2017-10-19 | criteria provided, single submitter | clinical testing | |
EGL Genetic Diagnostics, |
RCV000212245 | SCV000225181 | pathogenic | not provided | 2017-02-03 | criteria provided, single submitter | clinical testing | |
Color | RCV000129627 | SCV000292121 | pathogenic | Hereditary cancer-predisposing syndrome | 2020-02-09 | criteria provided, single submitter | clinical testing | |
Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000212245 | SCV000296747 | pathogenic | not provided | 2019-03-30 | criteria provided, single submitter | clinical testing | The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and found in general population data that is consistent with pathogenicity. |
Consortium of Investigators of Modifiers of BRCA1/2 |
RCV000009910 | SCV000327312 | pathogenic | Breast-ovarian cancer, familial 2 | 2015-10-02 | criteria provided, single submitter | clinical testing | |
Illumina Clinical Services Laboratory, |
RCV000367838 | SCV000383728 | pathogenic | BRCA2-Related Disorders | 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 | 2017-02-23 | criteria provided, single submitter | clinical testing | |
Fulgent Genetics, |
RCV000009910 | SCV000575747 | pathogenic | Breast-ovarian cancer, familial 2 | 2016-02-12 | criteria provided, single submitter | clinical testing | |
Department of Pathology and Laboratory Medicine, |
RCV000034451 | SCV000592016 | pathogenic | Hereditary breast and ovarian cancer syndrome | 2015-07-28 | criteria provided, single submitter | clinical testing | |
Genetic Services Laboratory, |
RCV000009910 | SCV000593749 | pathogenic | Breast-ovarian cancer, familial 2 | 2016-05-16 | criteria provided, single submitter | clinical testing | |
ARUP Laboratories, |
RCV000999951 | SCV000602754 | pathogenic | not specified | 2018-11-20 | criteria provided, single submitter | clinical testing | The BRCA2 c.5946delT; p.Ser1982fs variant (also known as 6174delT) creates a frameshift and is predicted to result in a truncated protein or absent transcript. This variant is known to be 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 (see ClinVar and references therein). References: Link to ClinVar database for BRCA2 c.5946delT: https://www.ncbi.nlm.nih.gov/clinvar/variation/9325/ 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. Couch FJ et al. BRCA2 germline mutations in male breast cancer cases and breast cancer families. Nat Genet. 1996 May;13(1):123-5. 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. |
Department of Medical Genetics, |
RCV000009910 | SCV000605651 | pathogenic | Breast-ovarian cancer, familial 2 | 2015-07-01 | criteria provided, single submitter | clinical testing | |
Laboratory for Molecular Medicine, |
RCV000034451 | SCV000605785 | pathogenic | Hereditary breast and ovarian cancer syndrome | 2019-04-24 | criteria provided, single submitter | clinical testing | The p.Ser1982ArgfsX22 variant in BRCA2 is a founder mutation in the Ashkenazi Jewish population (Finkelman 2012) 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% (61/10364) of Ashkenazi Jewish and 0.01% (14/128890) of European chromosomes by gnomAD, http://gnomad.broadinstitute.org). 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 SCV000282418.1). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC based upon the predicted impact to the protein and presence in multiple affected individuals. 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). |
DNA and Cytogenetics Diagnostics Unit, |
RCV000009910 | SCV000744479 | pathogenic | Breast-ovarian cancer, familial 2 | 2015-09-21 | criteria provided, single submitter | clinical testing | |
Equipe Genetique des Anomalies du Developpement, |
RCV000009910 | SCV000803796 | pathogenic | Breast-ovarian cancer, familial 2 | 2017-11-07 | criteria provided, single submitter | clinical testing | |
Prevention |
RCV000212245 | SCV000805732 | pathogenic | not provided | 2016-03-03 | criteria provided, single submitter | clinical testing | |
Mendelics | RCV000034451 | SCV000838826 | pathogenic | Hereditary breast and 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 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] |
Integrated Genetics/Laboratory Corporation of America | RCV000034451 | SCV000918979 | pathogenic | Hereditary breast and 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, |
RCV000853327 | SCV000996186 | pathogenic | Hereditary Cancer 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. |
OMIM | RCV000009910 | SCV000030127 | pathogenic | Breast-ovarian cancer, familial 2 | 1995-12-21 | no assertion criteria provided | literature only | |
OMIM | RCV000009911 | SCV000030132 | risk factor | Pancreatic cancer 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 and 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 2 | 2013-01-15 | no assertion criteria provided | clinical testing | |
Gene |
RCV000044800 | SCV000086654 | pathologic | Familial cancer of breast | 2013-09-26 | no assertion criteria provided | curation | Converted during submission to Pathogenic. |
Breast Cancer Information Core |
RCV000009910 | SCV000146737 | pathogenic | Breast-ovarian cancer, familial 2 | 2002-05-29 | no assertion criteria provided | clinical testing | |
Pathway Genomics | RCV000009910 | SCV000189906 | pathogenic | Breast-ovarian cancer, familial 2 | 2014-07-24 | no assertion criteria provided | clinical testing | |
Curoverse | RCV000034451 | SCV000245334 | pathogenic | Hereditary breast and 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 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 and ovarian cancer syndrome | 2014-01-31 | no assertion criteria provided | research | |
Diagnostic Laboratory, |
RCV000009910 | SCV000733276 | pathogenic | Breast-ovarian cancer, familial 2 | no assertion criteria provided | clinical testing | ||
Mayo Clinic Genetic Testing Laboratories, |
RCV000212245 | SCV000778694 | pathogenic | not provided | 2017-01-27 | 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 | |
Gharavi Laboratory, |
RCV000212245 | SCV000809465 | pathogenic | not provided | 2018-09-16 | no assertion criteria provided | research | |
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne, |
RCV000785226 | SCV000923794 | pathogenic | Ovarian Neoplasms | 2018-12-01 | no assertion criteria provided | research |