Submissions for variant NM_000465.4(BARD1):c.1835A>T (p.Asp612Val)

gnomAD frequency: 0.00011  dbSNP: rs201140528

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131406	SCV000186382	likely benign	Hereditary cancer-predisposing syndrome	2019-11-05	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	RCV000590537	SCV000209853	uncertain significance	not provided	2024-03-08	criteria provided, single submitter	clinical testing	Observed in individuals with personal or family history of breast, ovarian, or colorectal cancer, as well as in controls (PMID: 26787654, 27153395, 26315354, 28640387, 32658311, 35595798); Published functional studies suggest a neutral effect: homology-directed repair activity similar to a wild type control (PMID: 30925164); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 28640387, 26315354, 26787654, 27153395, 27997549, 17550235, 35595798, 32658311, 33471991, 30925164, 35534704, 35957908, 38136308, 35768576)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000205160	SCV000259236	uncertain significance	Familial cancer of breast	2025-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 612 of the BARD1 protein (p.Asp612Val). This variant is present in population databases (rs201140528, gnomAD 0.02%). This missense change has been observed in individual(s) with personal and/or family history of breast and/or ovarian cancer. (PMID: 35534704, 35595798, 35957908). ClinVar contains an entry for this variant (Variation ID: 142336). 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). Studies have shown that this missense change is associated with inconclusive levels of altered 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.
Counsyl	RCV000205160	SCV000785057	uncertain significance	Familial cancer of breast	2017-03-28	criteria provided, single submitter	clinical testing
Mendelics	RCV004700450	SCV000837952	likely benign	Hereditary cancer	2024-09-11	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following: it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease, and/or has normal protein function, and/or has lack of segregation with disease, and/or has been detected in co-occurrence with known pathogenic variant, and/or has lack of disease association in case-control studies, and/or is located in a region inconsistent with a known cause of pathogenicity.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000590537	SCV000888801	uncertain significance	not provided	2024-03-22	criteria provided, single submitter	clinical testing	The BARD1 c.1835A>T (p.Asp612Val) variant has been reported in individuals with breast cancer (PMIDs: 35534704 (2022), 35595798 (2022), 35957908 (2022), 32658311 (2021), 33471991 (2021), 27153395 (2016), see also LOVD (http://databases.lovd.nl/shared/)) and colorectal cancer (PMID: 28640387 (2017)). It has also been reported in reportedly healthy individuals (PMID: 26315354 (2015), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/)). In addition, a functional study indicated that this variant showed DNA repair activity comparable to the wild type (PMID: 30925164 (2019)). The frequency of this variant in the general population, 0.00023 (8/35430 chromosomes in Latino/Admixed American subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Based on the available information, we are unable to determine the clinical significance of this variant.
Fulgent Genetics, Fulgent Genetics	RCV000205160	SCV000895387	uncertain significance	Familial cancer of breast	2018-10-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131406	SCV000902723	likely benign	Hereditary cancer-predisposing syndrome	2016-02-09	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001174675	SCV001337907	uncertain significance	not specified	2024-08-05	criteria provided, single submitter	clinical testing	Variant summary: BARD1 c.1835A>T (p.Asp612Val) results in a non-conservative amino acid change located in the BRCT domain (IPR001357) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.5e-05 in 257966 control chromosomes, predominantly at a frequency of 0.00023 within the Latino subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1835A>T has been reported in the literature in individuals affected with breast, ovarian, colon, or prostate cancer without strong evidence of causality (Ramus_2015, Young_2016, Ricker_2017, Akcay_2021, Benito-Sanchez_2022, Gifoni_2022, Dillon_2022). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (Adamovich_2019). The following publications have been ascertained in the context of this evaluation (PMID: 26315354, 26787654, 27153395, 28640387, 30925164, 32658311, 35595798, 35957908, 35768576). ClinVar contains an entry for this variant (Variation ID: 142336). Based on the evidence outlined above, the variant was classified as uncertain significance.
Genetic Services Laboratory, University of Chicago	RCV001174675	SCV002067829	uncertain significance	not specified	2020-02-06	criteria provided, single submitter	clinical testing	DNA sequence analysis of the BARD1 gene demonstrated a sequence change, c.1835A>T, in exon 9 that results in an amino acid change, p.Asp612Val. This sequence change does not appear to have been previously described in patients with BARD1-related disorders and has been described in the gnomAD database with a frequency of 0.023% in Latino populations (dbSNP rs201140528). The p.Asp612Val change affects a poorly conserved amino acid residue located in a domain of the BARD1 protein that is known to be functional. The p.Asp612Val substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to the lack of functional studies, the clinical significance of the p.Asp612Val change remains unknown at this time.
Sema4, Sema4	RCV000131406	SCV002529554	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-30	criteria provided, single submitter	curation
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000205160	SCV002584625	uncertain significance	Familial cancer of breast	2022-07-07	criteria provided, single submitter	clinical testing	The BARD1 c.1835A>T (p.Asp612Val) missense change has a maximum subpopulation frequency of 0.023% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). Two individuals with this variant are reported in a database of women older than 70 years of age who have never had cancer (FLOSSIES, https://whi.color.com/). The in silico tool REVEL predicts a benign effect on protein function and functional analysis indicates that this variant has similar homology-directed repair compared to the wild-type (PMID: 30925164). This variant has been reported in an individual with early-onset breast cancer (PMID: 26787654) and in an individual with early-onset colorectal cancer (PMID: 28640387). 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.
Myriad Genetics, Inc.	RCV000205160	SCV004019245	likely benign	Familial cancer of breast	2023-02-24	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].
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492619	SCV004239913	likely benign	Breast and/or ovarian cancer	2023-04-25	criteria provided, single submitter	clinical testing