ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.8904del (p.Val2969fs) (rs80359730)

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Total submissions: 20
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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) RCV000031775 SCV000282464 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 RCV000045650 SCV000073663 pathogenic Hereditary breast and ovarian cancer syndrome 2018-12-20 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Val2969Cysfs*7) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with prostate cancer (PMID: 21952622, 23035815), as well as individuals with a personal and/or family history of breast cancer (PMID: 9667259, 15026808, 28284943). This variant is also known as 9132delC in the literature. ClinVar contains an entry for this variant (Variation ID: 38192). Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000131370 SCV000186346 pathogenic Hereditary cancer-predisposing syndrome 2019-03-11 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense);Rarity in general population databases (dbsnp, esp, 1000 genomes)
Michigan Medical Genetics Laboratories,University of Michigan RCV000031775 SCV000267823 pathogenic Breast-ovarian cancer, familial 2 2016-04-21 criteria provided, single submitter clinical testing
GeneDx RCV000216861 SCV000278884 pathogenic not provided 2018-11-16 criteria provided, single submitter clinical testing This deletion of one nucleotide is denoted BRCA2 c.8904delC at the cDNA level and p.Val2969CysfsX7 (V2969CfsX7) at the protein level. The normal sequence, with the base that is deleted in brackets, is CAAC[delC]GTGT. The deletion causes a frameshift, which changes a Valine to a Cysteine at codon 2969, and creates a premature stop codon at position 7 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRCA2 c.8904delC, previously reported as 9132delC, has been observed in families with hereditary breast and/or ovarian cancer (Frank 1998, Claes 2004) and in multiple individuals with a personal history of prostate cancer (Kote-Jarai 2011, Willems-Jones 2012, Castro 2013, Cheng 2016). This variant has been reported as a recurrent variant in the Belgian population (Claes 2004, Janavicus 2010) and is considered pathogenic.
Color RCV000131370 SCV000292151 pathogenic Hereditary cancer-predisposing syndrome 2015-04-07 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000735615 SCV000324883 pathogenic Breast and/or ovarian cancer 2016-02-11 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031775 SCV000327985 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Cancer Genetics and Genomics Laboratory,British Columbia Cancer Agency RCV000045650 SCV000586987 pathogenic Hereditary breast and ovarian cancer syndrome 2017-04-18 criteria provided, single submitter clinical testing
Department of Pathology and Molecular Medicine,Queen's University RCV000045650 SCV000588123 pathogenic Hereditary breast and ovarian cancer syndrome 2017-04-20 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000045650 SCV000592235 pathogenic Hereditary breast and ovarian cancer syndrome 2015-03-27 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000216861 SCV000600830 pathogenic not provided 2017-02-20 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000045650 SCV000605797 pathogenic Hereditary breast and ovarian cancer syndrome 2016-08-15 criteria provided, single submitter clinical testing The p.Val2969fs variant in BRCA2 has been reported at least 40 individuals with BRCA2-associated cancers (Claes 2004, Kote-Jarai 2011, Frank 1998, Breast Cancer Information Core (BIC) database). While this variant was absent from large popu lation studies, the ability of these studies to accurately detect indels may be limited. This variant is predicted to cause a frameshift, which alters the prote in?s amino acid sequence beginning at position 2969 and leads to a premature ter mination codon 7 amino acids downstream. This alteration is then predicted to le ad to a truncated or absent protein. Heterozygous loss of function of the BRCA2 gene is an established disease mechanism in hereditary breast and ovarian cancer (HBOC). In addition, this variant was classified as Pathogenic on April 22, 201 6 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000282464.1). In summa ry, the p.Val2969fs variant meets our criteria to be classified as pathogenic fo r HBOC in an autosomal dominant manner based upon the predicted impact to the pr otein.
PreventionGenetics,PreventionGenetics RCV000216861 SCV000805789 pathogenic not provided 2018-01-04 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000045650 SCV000918986 pathogenic Hereditary breast and ovarian cancer syndrome 2017-12-18 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.8904delC (p.Val2969CysfsX7) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA2 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 (e.g.c.9097dupA/p.Thr3033fsX11, c.9097delA/p.Thr3033fsX29, ). One in silico tool predicts a damaging outcome for this variant. This variant has been reported in numerous HBOC and prostate cancer patients and is absent in 244328 control chromosomes in gnomAD. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001002404 SCV001160334 pathogenic not specified 2019-02-23 criteria provided, single submitter clinical testing The BRCA2 c.8904delC; p.Val2969fs variant (rs80359730), also known as 9132delC for traditional nomenclature, is reported in the literature in individuals with breast, ovarian, or prostate cancer (Claes 2004, Frank 1998, Kote-Jarai 2011). This variant is classified as pathogenic by an expert review panel in ClinVar (Variation ID: 38192). It is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. 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: Claes K et al. BRCA1 and BRCA2 germline mutation spectrum and frequencies in Belgian breast/ovarian cancer families. Br J Cancer. 2004 Mar 22;90(6):1244-51. Frank TS et al. Sequence analysis of BRCA1 and BRCA2: correlation of mutations with family history and ovarian cancer risk. J Clin Oncol. 1998 Jul;16(7):2417-25. Kote-Jarai Z et al. BRCA2 is a moderate penetrance gene contributing to young-onset prostate cancer: implications for genetic testing in prostate cancer patients. Br J Cancer. 2011 Oct 11;105(8):1230-4.
Sharing Clinical Reports Project (SCRP) RCV000031775 SCV000054383 pathogenic Breast-ovarian cancer, familial 2 2012-12-03 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031775 SCV000147482 pathogenic Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000045650 SCV000587975 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000735615 SCV000863753 pathogenic Breast and/or ovarian cancer 2015-09-11 no assertion criteria provided clinical testing

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