Total submissions: 48
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Evidence- |
RCV000031625 | SCV000282424 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 2 | 2016-04-22 | reviewed by expert panel | curation | Variant allele predicted to encode a truncated non-functional protein. |
Labcorp Genetics |
RCV000044934 | SCV000072947 | pathogenic | Hereditary breast ovarian cancer syndrome | 2025-01-14 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Asn2135Lysfs*3) 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 (rs80359584, gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast, ovarian, and prostate cancer (PMID: 8988179, 11179017, 17063270, 21324516, 21952622, 25802882, 26026974). This variant is also known as c.6402_6406delTAACT, 6630del5, and 6633del5. ClinVar contains an entry for this variant (Variation ID: 38043). For these reasons, this variant has been classified as Pathogenic. |
Gene |
RCV000160301 | SCV000210779 | pathogenic | not provided | 2022-11-28 | criteria provided, single submitter | clinical testing | 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; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at a significant frequency in large population cohorts (gnomAD); Also known as 6633_6637delCTTAA and 6633del5; This variant is associated with the following publications: (PMID: 21324516, 21952622, 11179017, 12845657, 10326698, 27425403, 30287823, 34657373, 32980694, 9971877, 8988179, 25863477, 26026974, 25802882, 26687385, 25330149, 26843898, 26439132, 17063270, 18489799, 19967274, 20104584, 24156927, 16684319, 10464601, 12442265, 28127413, 28152038, 28985766, 29161300, 28831036, 28324225, 28724667, 28993434, 29909963, 30720863, 30078507, 30262796, 30720243, 30702160, 31090900, 27741520, 29625052, 26689913, 32318955, 31447099, 32581362, 33646313, 33151324, 34399810, 31825140, 32719484, 30875412, 30787465, 31742824, 33087929, 32359129, 32853339, 32341426, 32438681, 30040829, 35264596, 33804961, 32772980, 32986223) |
Ambry Genetics | RCV000162930 | SCV000213417 | pathogenic | Hereditary cancer-predisposing syndrome | 2025-01-24 | criteria provided, single submitter | clinical testing | The c.6405_6409delCTTAA (p.N2135Kfs*3) alteration, located in exon 11 (coding exon 10) of the BRCA2 gene, consists of a deletion of 5 nucleotides from position 6405 to 6409, causing a translational frameshift with a predicted alternate stop codon after 3 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 <0.001% (1/240630) total alleles studied. This alteration has been identified in multiple patients and families with hereditary breast and ovarian cancer syndrome (Gayther, 1997; Zhang, 2011; Kote-Jarai, 2011; de Juan, 2015; Alemar, 2016; Meisel, 2017; Li, 2018). Of note, this alteration is also designated as 6405delCTTAA, 6630del5, and 6633del5 in published literature. Based on the available evidence, this alteration is classified as pathogenic. |
Laboratory of Molecular Diagnosis of Cancer, |
RCV000240801 | SCV000265903 | pathogenic | Breast neoplasm | 2015-11-01 | criteria provided, single submitter | research | |
Color Diagnostics, |
RCV000162930 | SCV000292150 | pathogenic | Hereditary cancer-predisposing syndrome | 2024-07-23 | criteria provided, single submitter | clinical testing | This variant deletes 5 nucleotides in exon 11 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant is also known as c.6402_6406del, 6630del5, and 6633del5 in the literature. This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 8988179, 11179017, 17063270, 18489799, 21324516, 25802882, 27425403, 29161300, 30287823). This variant has been identified in 1/240630 chromosomes in the general population 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 | RCV000160301 | SCV000296661 | pathogenic | not provided | 2023-09-19 | criteria provided, single submitter | clinical testing | The BRCA2 c.6405_6409del (p.Asn2135Lysfs*3) variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. This variant has been reported in the published literature in multiple affected individuals and families with breast and/or ovarian cancer (PMIDs: 36169650 (2022), 33646313 (2021), 33151324 (2021), 32341426 (2020), 32318955 (2020), 31825140 (2019), 31742824 (2020), 31090900 (2019), 30720863 (2019), 30287823 (2018), 30262796 (2018), 30078507 (2018), 29625052 (2018), 29161300 (2017), 28993434 (2018), 28831036 (2017), 28724667 (2017), 28324225 (2017), 27741520 (2016), 27425403 (2016), 21324516 (2011), 18489799 (2008), 17063270 (2007), 11179017 (2001), and 8988179 (1997)). The variant has been reported in breast cancer cases as well as in a control individual in a large scale breast cancer association study (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/BRCA2)). It has also been seen in biliary tract cancer (PMID: 36243179 (2022)), prostate cancer (PMIDs: 21952622 (2011) and 32853339 (2021)), and pancreatic cancer (PMID: 34399810 (2021)). The frequency of this variant in the general population, 0.0000042 (1/240630 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. |
Consortium of Investigators of Modifiers of BRCA1/2 |
RCV000031625 | SCV000327416 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 2 | 2015-10-02 | criteria provided, single submitter | clinical testing | |
Baylor Genetics | RCV000456954 | SCV000541014 | pathogenic | Familial cancer of breast | 2024-03-03 | criteria provided, single submitter | clinical testing | |
Laboratory for Molecular Medicine, |
RCV000044934 | SCV000605796 | pathogenic | Hereditary breast ovarian cancer syndrome | 2019-04-24 | criteria provided, single submitter | clinical testing | The p.Asn2135LysfsX3 variant in BRCA2 has been reported in at least 12 individuals with BRCA2-associated cancers (Gayther 1997, Wagner 1999, Risch 2001, Gomes 2007, Machackova 2008, Kote-Jarai 2011, Zhang 2011, de Juan 2015, Hirotsu 2015, Breast Cancer Information Core database:www.research.nhgri.nih.gov/bic/). This variant has also been identified in 1/240630 of pan-ethnic chromosomes by gnomAD (http://gnomad.broadinstitute.org). This frequency is low enough to be consistent with the frequency of hereditary breast and ovarian cancer (HBOC) in the general population. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 2135 and leads to a premature termination codon 3 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA2 gene is an established disease mechanism in autosomal dominant HBOC. In addition, this variant was classified as Pathogenic on April 22, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000282424.1). In summary, this variant meets criteria to be classified as pathogenic for HBOC in an autosomal dominant manner based upon the predicted impact to the protein, presence in multiple affected individuals and very low frequency in the general population. ACMG/AMP Criteria applied: PVS1, PS4_Moderate, PM2. |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000044934 | SCV000694970 | pathogenic | Hereditary breast ovarian cancer syndrome | 2021-01-09 | criteria provided, single submitter | clinical testing | Variant summary: BRCA2 c.6405_6409delCTTAA (p.Asn2135LysfsX3) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4.2e-06 in 240630 control chromosomes. c.6405_6409delCTTAA has been widely reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. Multiple clinical diagnostic laboratories and one expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
Clinical Genetics DNA and cytogenetics Diagnostics Lab, |
RCV000031625 | SCV000744491 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 2 | 2017-05-31 | criteria provided, single submitter | clinical testing | |
3DMed Clinical Laboratory Inc | RCV000677858 | SCV000804019 | pathogenic | Malignant tumor of pancreas | 2017-11-20 | criteria provided, single submitter | clinical testing | |
Academic Department of Medical Genetics, |
RCV000162930 | SCV000992214 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2018-01-26 | criteria provided, single submitter | research | Application of AMCG guidelines 2015. Used other ClinVar submission evidence where relevant. Loss of heterozygosity in tumours or immunohistochemistry abnormalities considered functional evidence of pathogenicity. |
Mendelics | RCV000031625 | SCV001139150 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 2 | 2019-05-28 | criteria provided, single submitter | clinical testing | |
ARUP Laboratories, |
RCV000160301 | SCV001160240 | pathogenic | not provided | 2024-09-12 | criteria provided, single submitter | clinical testing | The BRCA2 c.6405_6409del; p.Asn2135LysfsTer3 variant (rs80359584) is reported in the medical literature in individuals with breast cancer or hereditary breast and ovarian cancer syndrome (Alemar 2016, Deng 2019, Momozawa 2018, Wen 2018, Whitworth 2018). This variant is only observed on one allele (1/240,630 chromosomes) in the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. This variant causes a frameshift by deleting five nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Considering available information, this variant is considered to be pathogenic. References: Alemar B et al. Prevalence of Hispanic BRCA1 and BRCA2 mutations among hereditary breast and ovarian cancer patients from Brazil reveals differences among Latin American populations. Cancer Genet. 2016 Sep;209(9):417-422. PMID: 27425403. Deng M et al. Prevalence and clinical outcomes of germline mutations in BRCA1/2 and PALB2 genes in 2769 unselected breast cancer patients in China. Int J Cancer. 2019 Sep 15;145(6):1517-1528. PMID: 30720863. Momozawa Y et al. Germline pathogenic variants of 11 breast cancer genes in 7,051 Japanese patients and 11,241 controls. Nat Commun. 2018 Oct 4;9(1):4083. PMID: 30287823. Wen WX et al. Inherited mutations in BRCA1 and BRCA2 in an unselected multiethnic cohort of Asian patients with breast cancer and healthy controls from Malaysia. J Med Genet. 2018 Feb;55(2):97-103. PMID: 28993434. Whitworth J et al. Comprehensive Cancer-Predisposition Gene Testing in an Adult Multiple Primary Tumor Series Shows a Broad Range of Deleterious Variants and Atypical Tumor Phenotypes. Am J Hum Genet. 2018 Jul 5;103(1):3-18. PMID: 29909963. |
Institute of Genomics, |
RCV000031625 | SCV001430701 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 2 | criteria provided, single submitter | research | ||
Institute of Medical Genetics and Applied Genomics, |
RCV000160301 | SCV001446832 | pathogenic | not provided | 2020-10-23 | criteria provided, single submitter | clinical testing | |
Clinical Genetics and Genomics, |
RCV000160301 | SCV001450398 | pathogenic | not provided | 2019-01-15 | criteria provided, single submitter | clinical testing | |
Department of Molecular Diagnostics, |
RCV001310128 | SCV001499676 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 1 | 2020-04-02 | criteria provided, single submitter | clinical testing | |
Institute for Clinical Genetics, |
RCV000160301 | SCV002010339 | pathogenic | not provided | 2021-11-03 | criteria provided, single submitter | clinical testing | |
Revvity Omics, |
RCV000160301 | SCV002020299 | pathogenic | not provided | 2022-11-29 | criteria provided, single submitter | clinical testing | |
CHEO Genetics Diagnostic Laboratory, |
RCV001271044 | SCV002043339 | pathogenic | Breast and/or ovarian cancer | 2019-05-17 | criteria provided, single submitter | clinical testing | |
Greenwood Genetic Center Diagnostic Laboratories, |
RCV000160301 | SCV002051607 | pathogenic | not provided | 2021-03-02 | criteria provided, single submitter | clinical testing | PVS1, PS4 |
DASA | RCV001849286 | SCV002107098 | pathogenic | BRCA2-related disorder | 2022-03-05 | criteria provided, single submitter | clinical testing | The c.6405_6409del;p.(Asn2135Lysfs*3) is a null frameshift variant (NMD) in the BRCA2 gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevant exon to the transcript - PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 38043; PMID: 21324516) - PS4. This variant is not present in population databases (rs80359584- gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. In summary, the currently available evidence indicates that the variant is pathogenic. |
Sema4, |
RCV000162930 | SCV002536231 | pathogenic | Hereditary cancer-predisposing syndrome | 2021-11-22 | criteria provided, single submitter | curation | |
Ce |
RCV000160301 | SCV004042561 | pathogenic | not provided | 2023-09-01 | criteria provided, single submitter | clinical testing | BRCA2: PVS1, PM2, PS4:Moderate |
Mayo Clinic Laboratories, |
RCV000160301 | SCV004226599 | pathogenic | not provided | 2024-01-30 | criteria provided, single submitter | clinical testing | PM5_strong, PVS1 |
All of Us Research Program, |
RCV004803060 | SCV004844257 | pathogenic | BRCA2-related cancer predisposition | 2024-09-16 | criteria provided, single submitter | clinical testing | The c.6405_6409del (p.Asn2135Lysfs*3) variant in the BRCA2 gene is located on the exon 11 and is predicted to cause shift of reading frame that introduces a premature translation termination codon (p.Asn2135Lysfs*3), resulting in an absent or disrupted protein product. The variant has been reported in multiple individuals with breast or ovarian cancer (PMID: 36171877, 31706072, 33606809, 30287823). Loss-of-function variants of BRCA2 are known to be pathogenic (PMID: 8988179, 11897832, 29446198). The variant is reported in ClinVar as pathogenic (ID: 38043) and reviewed by the expert panel. The variant is rare in the general population according to gnomAD (1/240630). Therefore, the c.6405_6409del (p.Asn2135Lysfs*3) variant of BRCA2 has been classified as pathogenic. |
Clinical Genetics Laboratory, |
RCV000160301 | SCV005198261 | pathogenic | not provided | 2022-05-27 | criteria provided, single submitter | clinical testing | |
Fulgent Genetics, |
RCV005007914 | SCV005633951 | 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 | 2024-03-25 | criteria provided, single submitter | clinical testing | |
Genomics and Molecular Medicine Service, |
RCV005237443 | SCV005882946 | pathogenic | Inherited breast cancer and ovarian cancer | 2024-10-16 | criteria provided, single submitter | clinical testing | PVS1,PM5_Strong |
Institute of Human Genetics, |
RCV000160301 | SCV006082268 | pathogenic | not provided | 2025-05-30 | criteria provided, single submitter | clinical testing | This variant has been identified by standard clinical testing. Female patient with triple-negative breast cancer Selected ACMG criteria: Not enough evidence |
Sharing Clinical Reports Project |
RCV000031625 | SCV000054232 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 2 | 2012-07-02 | no assertion criteria provided | clinical testing | |
Breast Cancer Information Core |
RCV000031625 | SCV000146844 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 2 | 2002-05-29 | no assertion criteria provided | clinical testing | |
Institute of Human Genetics, |
RCV000031625 | SCV000212026 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 2 | 2015-02-11 | no assertion criteria provided | clinical testing | |
Research Molecular Genetics Laboratory, |
RCV000044934 | SCV000587843 | pathogenic | Hereditary breast ovarian cancer syndrome | 2014-01-31 | no assertion criteria provided | research | |
Department of Pathology and Laboratory Medicine, |
RCV000031625 | SCV000592048 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 2 | no assertion criteria provided | clinical testing | The BRCA2 p.Asn2135Lysfs*3 variant was identified in 12 of 11758 proband chromosomes (frequency: 0.001) from individuals or families with breast, ovarian, and prostate cancer (Borg 2010, de Juan 2015, Gayther 1997, Kote-Jarai 2011, Zhang 2011). The variant was also identified in dbSNP (ID: rs80359584) as “With Pathogenic allele”, in ClinVar (classified as pathogenic by Color Genomics, Invitae, GeneDx, Ambry Genetics, SCRP, BIC, and 11 clinical laboratories), COGR, LOVD 3.0, UMD-LSDB (67x causal), BIC Database (13x clinically important), and in ARUP Laboratories (definitely pathogenic). The variant was not identified in Cosmic, or the Zhejiang University Database, the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.6405_6409del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 2135 and leads to a premature stop codon at position 2137. 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 breast and ovarian cancer and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. | |
Diagnostic Laboratory, |
RCV000031625 | SCV000733282 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 2 | no assertion criteria provided | clinical testing | ||
Counsyl | RCV000031625 | SCV000785311 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 2 | 2017-07-05 | no assertion criteria provided | clinical testing | This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. |
CZECANCA consortium | RCV001271044 | SCV001451863 | pathogenic | Breast and/or ovarian cancer | 2019-06-11 | no assertion criteria provided | clinical testing | |
Medical Genetics Laboratory, |
RCV001642418 | SCV001852765 | pathogenic | Breast carcinoma | 2021-09-11 | no assertion criteria provided | clinical testing | |
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, |
RCV000160301 | SCV001958038 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
Laboratory for Genotyping Development, |
RCV003162277 | SCV002758337 | pathogenic | Gastric cancer | 2021-07-01 | no assertion criteria provided | research | |
Zotz- |
RCV000031625 | SCV004171660 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 2 | 2023-11-24 | no assertion criteria provided | clinical testing | |
BRCAlab, |
RCV000031625 | SCV004243716 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 2 | 2020-03-02 | no assertion criteria provided | clinical testing | |
Molecular Oncology, |
RCV000031625 | SCV005061335 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 2 | 2021-05-24 | no assertion criteria provided | case-control | |
Prevention |
RCV001849286 | SCV005358611 | pathogenic | BRCA2-related disorder | 2024-08-16 | no assertion criteria provided | clinical testing | The BRCA2 c.6405_6409del5 variant is predicted to result in a frameshift and premature protein termination (p.Asn2135Lysfs*3). In the literature, this variant may be referred to as N2135fs, 6630del5, 6633_6637delCTTAA, 6633del5, or rs80359584. This variant has been repeatedly reported in individuals with various cancers such as breast, ovarian, prostate, and acute leukemia (reported as 6630del5 in Table 1, Gayther et al. 1997. PubMed ID: 8988179; reported as 6633del5 in Table 1, Risch et al. 2001. PubMed ID: 11179017; Table 2, Lhotova et al. 2020. PubMed ID: 32295079; reported as rs80359584 in Table S3, Darst et al. 2021. PubMed ID: 32853339). This variant has been reported in 1 of over 240,000 individuals in gnomAD, indicating that it is rare. In ClinVar, this variant is interpreted as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/38043/). Frameshift variants in BRCA2 are expected to be pathogenic. Taken together, this variant is interpreted as pathogenic. |