Submissions for variant NM_000465.4(BARD1):c.776A>G (p.Asp259Gly)

gnomAD frequency: 0.00002  dbSNP: rs587780036

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212124	SCV000149552	uncertain significance	not provided	2024-09-09	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual undergoing hereditary cancer testing (PMID: 25318351); This variant is associated with the following publications: (PMID: 25318351)
Ambry Genetics	RCV000115643	SCV000214886	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-03	criteria provided, single submitter	clinical testing	The p.D259G variant (also known as c.776A>G), located in coding exon 4 of the BARD1 gene, results from an A to G substitution at nucleotide position 776. The aspartic acid at codon 259 is replaced by glycine, an amino acid with similar properties. This variant was observed in an individual with early onset-breast cancer amongst a cohort of 1781 non-Ashkenazi Jewish individuals undergoing BRCA1/2 gene testing based on a personal history of breast cancer (Tung N et al. Cancer, 2015 Jan;121:25-33). This variant was detected in a cohort 97 (35 African American and 62 European American) seemingly unrelated breast cancer cases (Bishop MR et al. PLoS One, 2020 Aug;15:e0238295). This variant was also identified in a cohort of 3579 African males diagnosed with prostate cancer who underwent multi-gene panel testing of 19 DNA repair and cancer predisposition genes (Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000197946	SCV000254587	uncertain significance	Familial cancer of breast	2025-01-21	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 259 of the BARD1 protein (p.Asp259Gly). This variant is present in population databases (rs587780036, gnomAD 0.002%). This missense change has been observed in individual(s) with breast cancer and/or prostate cancer (PMID: 25186627, 32832836, 32866190). ClinVar contains an entry for this variant (Variation ID: 127747). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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.
Color Diagnostics, LLC DBA Color Health	RCV000115643	SCV000682816	uncertain significance	Hereditary cancer-predisposing syndrome	2024-01-05	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with glycine at codon 259 of the BARD1 protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 25186627, 32866190), an individual affected with prostate cancer (PMID: 32832836), and in individual(s) who underwent hereditary cancer genetic testing (PMID: 25318351). In an international breast cancer case-control meta-analysis, this variant was detected in 2/60466 cases and 1/53461 unaffected controls (PMID: 33471991). This variant has been identified in 2/257946 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	RCV000781933	SCV000920364	uncertain significance	not specified	2017-09-07	criteria provided, single submitter	clinical testing	Variant summary: The BARD1 c.776A>G (p.Asp259Gly) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant is absent in 115378 control chromosomes from ExAC. This variant has been reported in one BrC patient without strong evidence for causality. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212124	SCV001469364	uncertain significance	not provided	2019-10-21	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000197946	SCV005053311	uncertain significance	Familial cancer of breast	2024-03-27	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000197946	SCV005405376	likely benign	Familial cancer of breast	2024-07-22	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].