Submissions for variant NM_000465.4(BARD1):c.76A>G (p.Met26Val)

gnomAD frequency: 0.00004  dbSNP: rs587781570

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129604	SCV000184390	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-21	criteria provided, single submitter	clinical testing	The p.M26V variant (also known as c.76A>G), located in coding exon 1 of the BARD1 gene, results from an A to G substitution at nucleotide position 76. The methionine at codon 26 is replaced by valine, an amino acid with highly similar properties. This variant was identified in a cohort of 3,579 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 highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000546893	SCV000633065	uncertain significance	Familial cancer of breast	2024-01-17	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 26 of the BARD1 protein (p.Met26Val). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with BARD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 141201). 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 tolerated. 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	RCV000129604	SCV000682814	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-30	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with valine at codon 26 of the BARD1 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 been reported in an individual affected with high-risk breast cancer (DOI: 10.1200/JCO.2022.40.16_suppl.e22525). This variant has been identified in 2/232836 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	RCV002265614	SCV002548031	uncertain significance	not specified	2022-05-27	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002265614	SCV002760261	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000546893	SCV005054602	uncertain significance	Familial cancer of breast	2024-02-09	criteria provided, single submitter	clinical testing
Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University	RCV003153417	SCV003843809	likely pathogenic	Ovarian cancer	2022-01-01	flagged submission	clinical testing