Submissions for variant NM_000465.4(BARD1):c.173G>A (p.Arg58Lys)

gnomAD frequency: 0.00001  dbSNP: rs774009993

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000462863	SCV000545629	uncertain significance	Familial cancer of breast	2023-11-14	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 58 of the BARD1 protein (p.Arg58Lys). This variant is present in population databases (rs774009993, gnomAD 0.002%). 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: 406775). 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 lysine 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	RCV000481113	SCV000567554	uncertain significance	not provided	2023-08-23	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); 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; This variant is associated with the following publications: (PMID: 18480049)
Ambry Genetics	RCV000574056	SCV000660797	uncertain significance	Hereditary cancer-predisposing syndrome	2022-06-10	criteria provided, single submitter	clinical testing	The p.R58K variant (also known as c.173G>A), located in coding exon 2 of the BARD1 gene, results from a G to A substitution at nucleotide position 173. The arginine at codon 58 is replaced by lysine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species, and lysine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000574056	SCV000903882	uncertain significance	Hereditary cancer-predisposing syndrome	2021-01-06	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with lysine at codon 58 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 2/251136 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.
Baylor Genetics	RCV000462863	SCV004215007	uncertain significance	Familial cancer of breast	2023-09-13	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV003493575	SCV004243126	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000462863	SCV005405235	likely benign	Familial cancer of breast	2024-07-18	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].