Submissions for variant NM_000465.4(BARD1):c.1838C>A (p.Ala613Glu)

gnomAD frequency: 0.00002  dbSNP: rs146629794

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000568292	SCV000665734	likely benign	Hereditary cancer-predisposing syndrome	2024-02-26	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000635905	SCV000757331	uncertain significance	Familial cancer of breast	2025-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 613 of the BARD1 protein (p.Ala613Glu). This variant is present in population databases (rs146629794, gnomAD 0.01%). 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: 481379). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The glutamic acid 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.
Color Diagnostics, LLC DBA Color Health	RCV000568292	SCV001359829	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-26	criteria provided, single submitter	clinical testing	This variant is located in 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 not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 3/282434 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.
GeneDx	RCV003313105	SCV004012369	uncertain significance	not provided	2024-10-22	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 23056176, 17550235)
Mayo Clinic Laboratories, Mayo Clinic	RCV003313105	SCV004225978	uncertain significance	not provided	2023-05-04	criteria provided, single submitter	clinical testing	BP4, PM2
PreventionGenetics, part of Exact Sciences	RCV004740334	SCV005348900	uncertain significance	BARD1-related disorder	2024-08-12	no assertion criteria provided	clinical testing	The BARD1 c.1838C>A variant is predicted to result in the amino acid substitution p.Ala613Glu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD, and has conflicting interpretations of pathogenicity in ClinVar ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/481379/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.