Submissions for variant NM_000465.4(BARD1):c.1973G>A (p.Arg658His)

gnomAD frequency: 0.00006  dbSNP: rs377227840

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000223283	SCV000273672	likely benign	Hereditary cancer-predisposing syndrome	2018-09-19	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	RCV000228912	SCV000284936	uncertain significance	Familial cancer of breast	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 658 of the BARD1 protein (p.Arg658His). This variant is present in population databases (rs377227840, gnomAD 0.03%). This missense change has been observed in individual(s) with breast cancer and/or uveal melanoma (PMID: 29769598, 35264596). ClinVar contains an entry for this variant (Variation ID: 230212). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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	RCV000589126	SCV000512249	likely benign	not provided	2019-09-03	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge
Color Diagnostics, LLC DBA Color Health	RCV000223283	SCV000688162	likely benign	Hereditary cancer-predisposing syndrome	2018-03-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000430001	SCV000696764	likely benign	not specified	2021-07-26	criteria provided, single submitter	clinical testing	Variant summary: BARD1 c.1973G>A (p.Arg658His) 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 8e-05 in 251370 control chromosomes, predominantly at a frequency of 0.00032 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 1.3 fold of the estimated maximal expected allele frequency for a pathogenic variant in BARD1 causing Hereditary Breast and Ovarian Cancer Syndrome phenotype (0.00025), suggesting that the variant is a benign polymorphism. In a large study evaluating breast cancer cases and controls in the Breast Cancer Association Consortium (BCAC) the variant was reported in 8/60466 cases, but was also found in 4/53461 controls (Dorling_2021 through LOVD). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. However, another missense variant affecting the same residues (c.1972C>T (p.Arg658Cys)) was classified as benign by our laboratory. Six other submitters have provided clinical-significance assessments for this variant in ClinVar after 2014 without evidence for independent evaluation, and classified the variant as VUS (n=3) or likely benign (n=3). Based on the evidence outlined above, the variant was classified as likely benign.
Mendelics	RCV003491968	SCV000837947	likely benign	Hereditary cancer	2024-01-23	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000589126	SCV001470363	uncertain significance	not provided	2019-12-05	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV002225516	SCV002505096	benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000223283	SCV002529561	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-28	criteria provided, single submitter	curation
PreventionGenetics, part of Exact Sciences	RCV003407748	SCV004115628	uncertain significance	BARD1-related condition	2024-01-30	criteria provided, single submitter	clinical testing	The BARD1 c.1973G>A variant is predicted to result in the amino acid substitution p.Arg658His. This variant has been reported in an individual with uveal melanoma that harbored variants in other genes (Table 1, Hajkova et al. 2018. PubMed ID: 29769598). This variant is reported in 0.031% of alleles in individuals of Latino descent in gnomAD. It has conflicting interpretations of benign, likely benign, and uncertain significance (https://preview.ncbi.nlm.nih.gov/clinvar/variation/230212/). Although we suspect 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.
Revvity Omics, Revvity	RCV000589126	SCV004234621	uncertain significance	not provided	2019-08-01	criteria provided, single submitter	clinical testing