ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.946A>G (p.Ser316Gly) (rs55874646)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000858932 SCV000077211 benign not provided 2019-03-05 criteria provided, single submitter clinical testing
Ambry Genetics RCV000130474 SCV000185340 likely benign Hereditary cancer-predisposing syndrome 2017-09-22 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other data supporting benign classification,Co-occurence with mutation in same gene (phase unknown)
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000768649 SCV000324825 uncertain significance Breast and/or ovarian cancer 2016-12-02 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000049198 SCV000403073 uncertain significance Hereditary breast and ovarian cancer syndrome 2016-06-14 criteria provided, single submitter clinical testing
GeneDx RCV000432519 SCV000512283 likely benign not specified 2017-11-27 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.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000432519 SCV000591309 likely benign not specified 2014-04-23 criteria provided, single submitter clinical testing
Counsyl RCV000031290 SCV000785231 uncertain significance Breast-ovarian cancer, familial 1 2017-06-22 criteria provided, single submitter clinical testing
Color RCV000130474 SCV000902799 benign Hereditary cancer-predisposing syndrome 2015-11-02 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000432519 SCV000916801 likely benign not specified 2018-09-17 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.946A>G (p.Ser316Gly) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.7e-05 in 277152 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer (4.7e-05 vs 0.001), allowing no conclusion about variant significance. The variant, c.946A>G, has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Judkins_2005, Lee_2008, Azzollini_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other pathogenic variants have been reported in the UMD database (BRCA1 c.3228_3229delAG, p.Gly1077ALafsX8; BRCA2 c.6209_6212delAAAG, p.Glu2070ValfsX10), providing supporting evidence for a benign role. Multiple functional studies showed no impact on splicing, no sensitivity increase to ionizing radiation and an HDR assay showed no significant changes from wild-type (Anczukow_2008, Cochran_2015, Lu_2015). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (VUS x3, likely benign x2, benign x1). Based on the evidence outlined above, the variant was classified as likely benign.
Sharing Clinical Reports Project (SCRP) RCV000031290 SCV000053895 benign Breast-ovarian cancer, familial 1 2009-03-18 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031290 SCV000143958 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing

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