Submissions for variant NM_000465.4(BARD1):c.499C>T (p.Pro167Ser)

gnomAD frequency: 0.00005  dbSNP: rs767584985

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000507466	SCV000600198	uncertain significance	not provided	2023-01-05	criteria provided, single submitter	clinical testing	To the best of our knowledge, the variant has not been reported in the published literature. The frequency of this variant in the general population, 0.00035 (12/34528 chromosomes in Latino/Admixed American subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000530483	SCV000633041	uncertain significance	Familial cancer of breast	2023-12-01	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 167 of the BARD1 protein (p.Pro167Ser). This variant is present in population databases (rs767584985, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. 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: 438896). 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.
Ambry Genetics	RCV000570552	SCV000665746	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-02	criteria provided, single submitter	clinical testing	The p.P167S variant (also known as c.499C>T), located in coding exon 4 of the BARD1 gene, results from a C to T substitution at nucleotide position 499. The proline at codon 167 is replaced by serine, an amino acid with similar properties. This amino acid position is well 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.
Color Diagnostics, LLC DBA Color Health	RCV000570552	SCV000903997	uncertain significance	Hereditary cancer-predisposing syndrome	2022-09-06	criteria provided, single submitter	clinical testing	This missense variant replaces proline with serine at codon 167 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 not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 12/250928 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	RCV003114633	SCV003800773	uncertain significance	not specified	2023-01-02	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000530483	SCV004217198	uncertain significance	Familial cancer of breast	2023-08-15	criteria provided, single submitter	clinical testing
GeneDx	RCV000507466	SCV005332842	uncertain significance	not provided	2023-11-12	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge