Submissions for variant NM_000465.4(BARD1):c.1268A>G (p.Lys423Arg)

gnomAD frequency: 0.00005  dbSNP: rs749383704

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166718	SCV000217528	likely benign	Hereditary cancer-predisposing syndrome	2024-03-27	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.
GeneDx	RCV000482421	SCV000569046	uncertain significance	not provided	2017-08-23	criteria provided, single submitter	clinical testing	This variant is denoted BARD1 c.1268A>G at the cDNA level, p.Lys423Arg (K423R) at the protein level, and results in the change of a Lysine to an Arginine (AAA>AGA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BARD1 Lys423Arg was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Lysine and Arginine share similar properties, this is considered a conservative amino acid substitution. BARD1 Lys423Arg occurs at a position where amino acids with properties similar to Lysine are tolerated across species and is not located in a known functional domain. In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether BARD1 Lys423Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000635819	SCV000757243	uncertain significance	Familial cancer of breast	2025-01-17	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 423 of the BARD1 protein (p.Lys423Arg). This variant is present in population databases (rs749383704, gnomAD 0.003%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 32039725, 35534704, 35980532). ClinVar contains an entry for this variant (Variation ID: 187034). 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.
Mendelics	RCV000635819	SCV000837967	uncertain significance	Familial cancer of breast	2018-07-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000166718	SCV000912089	uncertain significance	Hereditary cancer-predisposing syndrome	2020-02-21	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with arginine at codon 423 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with hereditary breast and ovarian cancer (PMID: 32039725). This variant has been identified in 1/250918 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.
Sema4, Sema4	RCV000166718	SCV002526998	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-18	criteria provided, single submitter	curation
PreventionGenetics, part of Exact Sciences	RCV003407620	SCV004112094	uncertain significance	BARD1-related disorder	2023-05-17	criteria provided, single submitter	clinical testing	The BARD1 c.1268A>G variant is predicted to result in the amino acid substitution p.Lys423Arg. This variant has been reported in an individual with clinical suspicion of hereditary breast and/or ovarian cancer (Table 2, da Costa e Silva Carvalho et al. 2020. PubMed ID: 32039725). This variant is reported in 1 of ~251,000 alleles in gnomAD (http://gnomad.broadinstitute.org/variant/2-215645330-T-C). It is interpreted as uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/187034/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Baylor Genetics	RCV000635819	SCV004214948	uncertain significance	Familial cancer of breast	2023-10-23	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000482421	SCV005625634	uncertain significance	not provided	2024-06-25	criteria provided, single submitter	clinical testing	The BARD1 c.1268A>G (p.Lys423Arg) variant has been reported in the published literature in individuals with breast and/or ovarian cancer (PMIDs: 32039725 (2020), 35534704 (2022), and 35980532 (2022)). The frequency of this variant in the general population, 0.000004 (1/250918 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000635819	SCV005689290	uncertain significance	Familial cancer of breast	2025-02-05	criteria provided, single submitter	clinical testing	The BARD1 c.1268A>G (p.Lys423Arg) missense change has a maximum subpopulation frequency of 0.003% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been reported in an individual with breast and/or ovarian cancer (PMID: 32039725). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.