ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.9770A>G (p.Lys3257Arg)

gnomAD frequency: 0.00016  dbSNP: rs55847618
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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001082226 SCV000073908 likely benign Hereditary breast ovarian cancer syndrome 2021-12-11 criteria provided, single submitter clinical testing
Ambry Genetics RCV000129187 SCV000183923 likely benign Hereditary cancer-predisposing syndrome 2018-12-18 criteria provided, single submitter clinical testing Co-occurence with mutation in same gene (phase unknown);In silico models in agreement (benign);Seen in trans with a mutation or in homozygous state in individual without severe disease for that gene
GeneDx RCV000586082 SCV000210518 likely benign not provided 2019-02-08 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 10923033, 26580448, 24817641, 23555315, 23320992, 22034289, 9971877)
Counsyl RCV000077474 SCV000489530 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 2 2016-10-18 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001818225 SCV000695271 likely benign not specified 2022-02-07 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.9770A>G (p.Lys3257Arg) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 251422 control chromosomes, predominantly at a frequency of 0.0008 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately equal to the estimated maximal expected allele frequency for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (0.00075), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.9770A>G has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Fackenthal_2012, Pal_2013). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrences with pathogenic variants have been reported (BRCA2 c.4712_4713delAG, p.Glu1571fsX3; BRCA2 c.6155dupC, p.Ser2053fsX7; Internal testing), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=4) and as benign/likely benign (n=5). Based on the evidence outlined above, the variant was classified as likely benign.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000586082 SCV000885115 uncertain significance not provided 2020-01-26 criteria provided, single submitter clinical testing The BRCA2 c.9770A>G; p.Lys3257Arg variant (rs55847618), also known as A9998G, is reported in the literature in individuals affected with breast cancer (Fackenthal 2012, Pal 2013). This variant is reported in ClinVar (Variation ID: 52897), and is found in the African population with an allele frequency of 0.07% (18/24972 alleles) in the Genome Aggregation Database. The lysine at codon 3257 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. However, due to limited information, the clinical significance of the p.Lys3257Arg variant is uncertain at this time. REFERENCES Fackenthal JD et al. High prevalence of BRCA1 and BRCA2 mutations in unselected Nigerian breast cancer patients. Int J Cancer. 2012 Sep 1;131(5):1114-23. Pal T et al. Early onset breast cancer in a registry-based sample of African-american women: BRCA mutation prevalence, and other personal and system-level clinical characteristics. Breast J. 2013 Mar-Apr;19(2):189-92.
Color Diagnostics, LLC DBA Color Health RCV000129187 SCV000902978 benign Hereditary cancer-predisposing syndrome 2016-04-22 criteria provided, single submitter clinical testing
Mendelics RCV000077474 SCV001139275 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 2 2019-05-28 criteria provided, single submitter clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State RCV001082226 SCV002025882 likely benign Hereditary breast ovarian cancer syndrome 2021-11-16 criteria provided, single submitter clinical testing
Genetic Services Laboratory,University of Chicago RCV001818225 SCV002067621 uncertain significance not specified 2021-02-26 criteria provided, single submitter clinical testing
Sema4,Sema4 RCV000129187 SCV002532061 likely benign Hereditary cancer-predisposing syndrome 2021-10-28 criteria provided, single submitter curation
Sharing Clinical Reports Project (SCRP) RCV000077474 SCV000109272 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 2 2009-08-12 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000077474 SCV000147709 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 2 2004-02-20 no assertion criteria provided clinical testing

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