Submissions for variant NM_000465.4(BARD1):c.665C>T (p.Ala222Val)

gnomAD frequency: 0.00006  dbSNP: rs142086060

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000538719	SCV000633053	uncertain significance	Familial cancer of breast	2024-12-28	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 222 of the BARD1 protein (p.Ala222Val). This variant is not present in population databases (gnomAD no frequency). 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: 460758). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (internal data). 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	RCV000568474	SCV000660816	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-21	criteria provided, single submitter	clinical testing	The c.665C>T (p.A222V) alteration is located in exon 4 (coding exon 4) of the BARD1 gene. This alteration results from a C to T substitution at nucleotide position 665, causing the alanine (A) at amino acid position 222 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588795	SCV000696781	uncertain significance	not provided	2016-11-18	criteria provided, single submitter	clinical testing	Variant summary: The BARD1 c.665C>T (p.Ala222Val) variant involves the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a benign outcome for this substitution (SNPs&GO not captured due to low reliability index). This variant is absent in 118148 control chromosomes. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Color Diagnostics, LLC DBA Color Health	RCV000568474	SCV000906454	uncertain significance	Hereditary cancer-predisposing syndrome	2022-07-06	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 222 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 1/229770 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	RCV000588795	SCV002039068	uncertain significance	not provided	2021-12-14	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (Lek et al., 2016); 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
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000588795	SCV005625680	uncertain significance	not provided	2024-05-15	criteria provided, single submitter	clinical testing	The BARD1 c.665C>T (p.Ala222Val) variant has not been reported in individuals with BARD1-related conditions in the published literature. The frequency of this variant in the general population, 0.0000044 (1/229770 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.
Fulgent Genetics, Fulgent Genetics	RCV000538719	SCV005648859	uncertain significance	Familial cancer of breast	2024-03-17	criteria provided, single submitter	clinical testing