ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.5946del (p.Ser1982fs) (rs80359550)

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Total submissions: 46
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) 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 2019-01-11 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.
GeneDx 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,University of Michigan RCV000009910 SCV000195993 pathogenic Breast-ovarian cancer, familial 2 2014-11-03 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000768632 SCV000219371 pathogenic Breast and/or ovarian cancer 2017-10-19 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000212245 SCV000225181 pathogenic not provided 2017-02-03 criteria provided, single submitter clinical testing
Color RCV000129627 SCV000292121 pathogenic Hereditary cancer-predisposing syndrome 2015-03-09 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 (CIMBA), c/o University of Cambridge RCV000009910 SCV000327312 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina 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.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center RCV000414179 SCV000492446 pathogenic Neoplasm of the breast 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,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,Sinai Health System RCV000034451 SCV000592016 pathogenic Hereditary breast and ovarian cancer syndrome 2015-07-28 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000009910 SCV000593749 pathogenic Breast-ovarian cancer, familial 2 2016-05-16 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, 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,Oslo University Hospital RCV000009910 SCV000605651 pathogenic Breast-ovarian cancer, familial 2 2015-07-01 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000034451 SCV000605785 pathogenic Hereditary breast and ovarian cancer syndrome 2017-03-31 criteria provided, single submitter clinical testing The p.Ser1982fs variant in BRCA2 is a founder mutation in the Ashkenazi Jewish p opulation (Finkelman 2012) and has been identified in >500 individuals of variou s ethnicities with BRCA2-associated cancers (Breast Cancer Information Core (BIC ) database: https://research.nhgri.nih.gov/projects/bic/). It has also been iden tified in 0.6% (59/10151) Ashkenazi Jewish chromosomes and 10/126512 European ch romosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitu te.org; dbSNP rs80359550). This variant is predicted to cause a frameshift, whic h 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 t hen predicted to lead to a truncated or absent protein. Heterozygous loss of fun ction of the BRCA2 gene is an established disease mechanism in individuals with hereditary breast and ovarian cancer (HBOC). Additionally, this variant was clas sified as pathogenic on April 22, 2016 by the ClinGen-approved ENIGMA expert pan el (ClinVar SCV000282418.1). In summary, the p.Ser1982fs variant meets criteria to be classified as pathogenic for HBOC in an autosomal dominant manner based up on the predicted impact to the protein and presence in multiple affected individ uals. ACMG/AMP Criteria applied (Richards 2015): PVS1, PS4_Strong.
Institute for Biomarker Research,Medical Diagnostic Laboratories, L.L.C. RCV000129627 SCV000679720 pathogenic Hereditary cancer-predisposing syndrome 2017-07-12 criteria provided, single submitter clinical testing
GeneKor MSA RCV000212245 SCV000693574 pathogenic not provided 2017-11-01 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000009910 SCV000744479 pathogenic Breast-ovarian cancer, familial 2 2015-09-21 criteria provided, single submitter clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV000009910 SCV000803796 pathogenic Breast-ovarian cancer, familial 2 2017-11-07 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics 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,Baylor College of Medicine 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, Rady Children's Hospital San Diego 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,National Institutes of Health 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 (SCRP) RCV000009910 SCV000054198 pathogenic Breast-ovarian cancer, familial 2 2013-01-15 no assertion criteria provided clinical testing
GeneReviews RCV000044800 SCV000086654 pathologic Familial cancer of breast 2013-09-26 no assertion criteria provided curation Converted during submission to Pathogenic.
Breast Cancer Information Core (BIC) (BRCA2) 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, Universidad de San Martín de Porres RCV000009910 SCV000263344 pathogenic Breast-ovarian cancer, familial 2 2015-06-10 no assertion criteria provided research
Bioscientia Institut fuer Medizinische Diagnostik GmbH,Sonic Healthcare RCV000044800 SCV000484936 pathogenic Familial cancer of breast no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000034451 SCV000587812 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000009910 SCV000733276 pathogenic Breast-ovarian cancer, familial 2 no assertion criteria provided clinical testing
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic 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,Columbia University RCV000212245 SCV000809465 pathogenic not provided 2018-09-16 no assertion criteria provided research
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785226 SCV000923794 pathogenic Ovarian Neoplasms 2018-12-01 no assertion criteria provided research

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