ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.2078A>G (p.Asp693Gly)

gnomAD frequency: 0.00001  dbSNP: rs756748588
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color Diagnostics, LLC DBA Color Health RCV000775170 SCV000909353 uncertain significance Hereditary cancer-predisposing syndrome 2022-02-01 criteria provided, single submitter clinical testing This missense variant replaces aspartic acid with glycine at codon 693 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 3/251186 chromosomes 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001193223 SCV001361940 uncertain significance not specified 2019-12-20 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.2078A>G (p.Asp693Gly) 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 1.2e-05 in 251186 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2078A>G in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported in the literature. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar (evaluation after 2014) and cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV001220512 SCV001392506 uncertain significance Hereditary breast ovarian cancer syndrome 2021-10-11 criteria provided, single submitter clinical testing 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA1 protein function. ClinVar contains an entry for this variant (Variation ID: 630129). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. This variant is present in population databases (rs756748588, ExAC 0.05%). This sequence change replaces aspartic acid with glycine at codon 693 of the BRCA1 protein (p.Asp693Gly). The aspartic acid residue is weakly conserved and there is a moderate physicochemical difference between aspartic acid and glycine.
University of Washington Department of Laboratory Medicine, University of Washington RCV000775170 SCV003849520 likely benign Hereditary cancer-predisposing syndrome 2023-03-23 criteria provided, single submitter curation Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).

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