Submissions for variant NM_000465.4(BARD1):c.2191C>T (p.Arg731Cys)

dbSNP: rs76744638

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000167289	SCV000218132	likely benign	Hereditary cancer-predisposing syndrome	2021-09-17	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.
Invitae	RCV000204878	SCV000259841	uncertain significance	Familial cancer of breast	2024-01-17	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 731 of the BARD1 protein (p.Arg731Cys). This variant is present in population databases (rs76744638, gnomAD 0.03%). This missense change has been observed in individual(s) with BARD1-related conditions (PMID: 25980754, 26757417, 28051113, 30093976). ClinVar contains an entry for this variant (Variation ID: 187551). 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. Experimental studies have shown that this missense change does not substantially affect BARD1 function (PMID: 30925164). 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	RCV000167289	SCV000537609	uncertain significance	Hereditary cancer-predisposing syndrome	2024-01-05	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 731 of the BARD1 protein. Computational prediction suggests that this variant may not impact protein structure and function. Functional studies have shown that this variant did not significantly impact protein expression and homology-directed repair activity compared to wild-type (PMID: 30925164). This variant has been observed in individuals with breast cancer (PMID: 26757417, 28051113, 30093976; DOI: 10.1200/JCO.2022.40.16_suppl.e22525) and an individual suspected of having Lynch syndrome (PMID: 25980754). This variant has also been identified in 12/282706 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	RCV000483971	SCV000570741	uncertain significance	not provided	2023-03-01	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate no significant reduction in homology-directed repair (HDR) activity compared to wild type and equal protein abundance compared to wild type (Adamovich et al., 2019); Observed in two individuals with bilateral retinoblastoma who both harbored a germline RB1 variant and another variant in BARD1 p.(T534I) on the same allele (in cis) (Rojanaporn et al., 2022); This variant is associated with the following publications: (PMID: 32091409, 25980754, 26757417, Wang2022[abstract], 30093976, 17550235, 28051113, 29292755, 30925164, 36173648)
Sema4, Sema4	RCV000167289	SCV002529587	uncertain significance	Hereditary cancer-predisposing syndrome	2021-06-12	criteria provided, single submitter	curation
Baylor Genetics	RCV000204878	SCV004217184	uncertain significance	Familial cancer of breast	2023-12-24	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000483971	SCV004222394	likely benign	not provided	2022-03-14	criteria provided, single submitter	clinical testing
Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University	RCV003153458	SCV003843790	likely pathogenic	Ovarian cancer	2022-01-01	flagged submission	clinical testing