ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.4981G>A (p.Glu1661Lys)

dbSNP: rs80357401
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000509960 SCV000607853 benign Hereditary cancer-predisposing syndrome 2021-01-15 criteria provided, single submitter clinical testing This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp RCV000416506 SCV000636001 uncertain significance Hereditary breast ovarian cancer syndrome 2023-10-27 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1661 of the BRCA1 protein (p.Glu1661Lys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 375447). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 30209399) indicates that this missense variant is not expected to disrupt BRCA1 function with a negative predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect BRCA1 function (PMID: 30209399). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000586506 SCV000699187 uncertain significance not provided 2016-11-17 criteria provided, single submitter clinical testing Variant summary: The c.4981G>A (p.Glu1661Lys) in BRCA1 gene is a missense change that involves a mildly conserved nucleotide and 3/5 in silico tools predict deleterious outcome. The variant of interest is located within BRCT functional domain and several neighboring missense variants are associated with HBOC, although the functional impact of this missense change is yet to be studied. The variant is absent from the large control population dataset of ExAC and has not, to our knowledge, been reported in affected individuals via published reports. In addition, one database cites the variant as VUS. At this time there is not sufficient undeniable evidence to classify this variant with confidence. Taken together, the variant was classified as VUS until more data becomes available.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000586506 SCV001133601 uncertain significance not provided 2020-07-10 criteria provided, single submitter clinical testing
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne RCV000416506 SCV004228255 uncertain significance Hereditary breast ovarian cancer syndrome 2023-10-19 criteria provided, single submitter curation PM2_sup (not in gnomAD), BS3 (Findlay et al. functional). According to the ACMG standard criteria we chose these criteria: PM2 (supporting pathogenic): Absent from gnomAD (PM2_sup), BS3 (strong benign): Findlay et al. Functional
Color Diagnostics, LLC DBA Color Health RCV000509960 SCV004360141 uncertain significance Hereditary cancer-predisposing syndrome 2022-02-15 criteria provided, single submitter clinical testing This missense variant replaces glutamic acid with lysine at codon 1661 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). This variant has been reported to be functional in a haploid cell proliferation assay (PMID: 30209399). To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Brotman Baty Institute, University of Washington RCV001077875 SCV001243871 not provided Breast-ovarian cancer, familial, susceptibility to, 1 no assertion provided in vitro

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