ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.6739A>G (p.Ser2247Gly) (rs80358896)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001079936 SCV000073047 likely benign Hereditary breast and ovarian cancer syndrome 2020-12-07 criteria provided, single submitter clinical testing
GeneDx RCV000045034 SCV000210633 likely benign not specified 2017-06-07 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics RCV000163090 SCV000213595 likely benign Hereditary cancer-predisposing syndrome 2019-02-09 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other data supporting benign classification
Counsyl RCV000031645 SCV000488677 uncertain significance Breast-ovarian cancer, familial 2 2016-05-20 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000045034 SCV000694991 likely benign not specified 2020-07-13 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.6739A>G (p.Ser2247Gly) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251430 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.6739A>G has been reported in the literature in individuals affected with Breast and/or Ovarian Cancer (example, Mavarki_1997, Haffty_2006, Haffty_2009, Lu_2012, Caux-Montcoutier_2009). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At-least three co-occurrences with other pathogenic variant(s) have been reported in the UMD database as well as at our laboratory (BRCA1 c.3700_3704delGTAAA, p.Val1234GlnfsX8; BRCA1 c.4524G>A, p.Trp1508*; BRCA1 c.5096G>A, p.Arg1699Gln), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign, n=4, benign, n=1, VUS, n=1) reflecting an emerging consensus towards a likely benign outcome. Based on the evidence outlined above, the variant was re-classified as likely benign.
Color Health, Inc RCV000163090 SCV000911017 benign Hereditary cancer-predisposing syndrome 2016-05-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000587555 SCV001470438 uncertain significance not provided 2020-05-18 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001286195 SCV001472727 uncertain significance none provided 2019-11-11 criteria provided, single submitter clinical testing The BRCA2 c.6739A>G; p.Ser2247Gly variant (rs80358896) is reported in the literature in multiple individuals affected with breast cancer, but often without specific phenotype information or with other unclassified variants in BRCA2 (Caux-Moncoutier 2009, Haffty 2006, Mavraki 1997). This variant is reported in ClinVar (Variation ID: 38063), and is found in the non-Finnish European population with an allele frequency of 0.0062% (8/129102 alleles) in the Genome Aggregation Database. The serine at codon 2247 is weakly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.324). Given the lack of clinical and functional data, the significance of the p.Ser2247Gly variant is uncertain at this time. References: Caux-Moncoutier V et al. Impact of BRCA1 and BRCA2 variants on splicing: clues from an allelic imbalance study. Eur J Hum Genet. 2009 Nov;17(11):1471-80. Haffty BG et al. Racial differences in the incidence of BRCA1 and BRCA2 mutations in a cohort of early onset breast cancer patients: African American compared to white women. J Med Genet. 2006 Feb;43(2):133-7. Mavraki E et al. Germline BRCA2 mutations in men with breast cancer. Br J Cancer. 1997;76(11):1428-31.
Sharing Clinical Reports Project (SCRP) RCV000031645 SCV000054252 likely benign Breast-ovarian cancer, familial 2 2011-02-25 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031645 SCV000146919 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000587555 SCV000778700 likely benign not provided 2017-02-17 no assertion criteria provided clinical testing

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