ClinVar Miner

Submissions for variant NM_000465.4(BARD1):c.2083G>A (p.Val695Ile)

gnomAD frequency: 0.00002  dbSNP: rs111367604
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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 RCV000130659 SCV000185545 likely benign Hereditary cancer-predisposing syndrome 2018-03-01 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: 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.
Invitae RCV000474704 SCV000545593 uncertain significance Familial cancer of breast 2022-10-29 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 695 of the BARD1 protein (p.Val695Ile). This variant is present in population databases (rs111367604, gnomAD 0.01%). This missense change has been observed in individual(s) with breast cancer and individuals undergoing clinical testing for hereditary breast and ovarian cancer (HBOC) (PMID: 26350354, 28709830). ClinVar contains an entry for this variant (Variation ID: 141937). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change does not substantially affect BARD1 function (PMID: 26350354). 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.
GeneDx RCV000484351 SCV000567438 uncertain significance not provided 2023-05-09 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies demonstrate no damaging effect: DNA repair activity comparable to wild type in a homology-directed repair (HDR) assay (Lee et al., 2015); This variant is associated with the following publications: (PMID: 17550235, 28709830, 26350354)
Color Diagnostics, LLC DBA Color Health RCV000130659 SCV000903151 likely benign Hereditary cancer-predisposing syndrome 2016-12-13 criteria provided, single submitter clinical testing
Sema4, Sema4 RCV000130659 SCV002529573 uncertain significance Hereditary cancer-predisposing syndrome 2021-09-30 criteria provided, single submitter curation
PreventionGenetics, part of Exact Sciences RCV003398765 SCV004105507 uncertain significance BARD1-related condition 2023-07-11 criteria provided, single submitter clinical testing The BARD1 c.2083G>A variant is predicted to result in the amino acid substitution p.Val695Ile. This variant has been reported in an individual with breast cancer that harbored variants in other genes (Schoolmeester et al. 2017. PubMed ID: 28709830, Table 1). Functional analysis using a homology-directed repair assay suggests this allele is functional (Lee et al.2015. PubMed ID: 26350354). This variant is reported in 0.0096% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-215593651-C-T) and has conflicting interpretations of likely benign and uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/141937/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000484351 SCV004222391 likely benign not provided 2023-06-19 criteria provided, single submitter clinical testing

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