ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.4882A>G (p.Met1628Val) (rs80357465)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130592 SCV000185465 likely benign Hereditary cancer-predisposing syndrome 2017-05-19 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Intact protein function observed in appropriate functional assay(s),In silico models in agreement (benign)
Breast Cancer Information Core (BIC) (BRCA1) RCV000112414 SCV000145200 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
CSER_CC_NCGL; University of Washington Medical Center RCV000148406 SCV000190105 uncertain significance Neoplasm of the breast 2014-06-01 criteria provided, single submitter research Low GERP score may suggest that this variant may belong in a lower pathogenicity class
CeGaT Praxis fuer Humangenetik Tuebingen RCV000761958 SCV000892185 uncertain significance not provided 2018-09-30 criteria provided, single submitter clinical testing
Color RCV000130592 SCV000910925 likely benign Hereditary cancer-predisposing syndrome 2015-01-17 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000212187 SCV000591544 likely benign not specified 2015-06-24 criteria provided, single submitter clinical testing
GeneDx RCV000212187 SCV000209979 likely benign not specified 2017-03-01 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.
Institute for Biomarker Research,Medical Diagnostic Laboratories, L.L.C. RCV000130592 SCV000747798 likely benign Hereditary cancer-predisposing syndrome 2018-01-16 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000212187 SCV000916723 uncertain significance not specified 2018-10-05 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.4882A>G (p.Met1628Val) 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 2.2e-05 in 277230 control chromosomes. The variant has been reported in the literature in HBOC patients without strong evidence for or against causality (Troudi_2007, Lu_2012, Durocher_1996). Functional studies are conflicting: one report suggests a loss of transcriptional activation similar to a null allele (Phelan_2005), whereas another study measured yeast colony size and found no difference when compared to a WT control (Coyne_2004). Other reports have classified the variant as a VUS (Iversen_2011) and as likely not pathogenic (Woods_2016) based on functional studies. Co-occurrences with other pathogenic variant(s) have been reported (BRCA1 c.25G>T, p.Glu9X), providing supporting evidence for a benign role. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, with classifications of likely benign and VUS. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.

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