Submissions for variant NM_000465.4(BARD1):c.1028C>T (p.Thr343Ile)

gnomAD frequency: 0.00003  dbSNP: rs201032007

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000235113	SCV000149517	uncertain significance	not provided	2024-08-09	criteria provided, single submitter	clinical testing	Observed in individuals with endometrial, ovarian, breast, or other cancers (PMID: 26315354, 27443514, 28717660, 34646395, 35595798); Published functional studies are inconclusive: decreased homology-directed repair activity, but not significantly different from the wild-type control (PMID: 30925164); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27443514, 26315354, 28717660, 34646395, 35595798, 32980694, 33471991, 25085752, 36243179, 30925164, 30306255)
Ambry Genetics	RCV000115608	SCV000184446	likely benign	Hereditary cancer-predisposing syndrome	2020-11-17	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000206115	SCV000259877	uncertain significance	Familial cancer of breast	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 343 of the BARD1 protein (p.Thr343Ile). This variant is present in population databases (rs201032007, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with breast cancer, endometrial cancer, and/or ovarian cancer (PMID: 26315354, 27443514, 34646395, 35595798). ClinVar contains an entry for this variant (Variation ID: 127712). 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.
Counsyl	RCV000206115	SCV000488955	uncertain significance	Familial cancer of breast	2016-07-26	criteria provided, single submitter	clinical testing
Mendelics	RCV000206115	SCV000837973	uncertain significance	Familial cancer of breast	2018-07-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115608	SCV000902712	likely benign	Hereditary cancer-predisposing syndrome	2020-11-30	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115608	SCV002526972	uncertain significance	Hereditary cancer-predisposing syndrome	2021-06-08	criteria provided, single submitter	curation
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000235113	SCV002774103	likely benign	not provided	2023-06-14	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000206115	SCV003806921	uncertain significance	Familial cancer of breast	2022-07-22	criteria provided, single submitter	clinical testing	ACMG classification criteria: PM2 moderated, BP4 supporting
Myriad Genetics, Inc.	RCV000206115	SCV004019269	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].
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV003320563	SCV004024862	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003320563	SCV005039777	uncertain significance	not specified	2024-03-19	criteria provided, single submitter	clinical testing	Variant summary: BARD1 c.1028C>T (p.Thr343Ile) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 1614100 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in BARD1 causing Breast Cancer (0.00012 vs 0.00025), allowing no conclusion about variant significance. c.1028C>T has been reported in the literature as a VUS in settings of multigene panel testing among individuals with a variety of cancers (example, Ramus_2015, Ring_2016, Bonache_2018, Laraqui_2021, Benito-Sanchez_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Breast and/or BARD1 associated Cancer. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant on Homology Directed Repair and damage sensitivity (Adamovich_2019). The following publications have been ascertained in the context of this evaluation (PMID: 30925164, 35595798, 30306255, 34646395, 26315354, 27443514). ClinVar contains an entry for this variant (Variation ID: 127712). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
PreventionGenetics, part of Exact Sciences	RCV003891610	SCV000806096	uncertain significance	BARD1-related disorder	2024-01-12	no assertion criteria provided	clinical testing	The BARD1 c.1028C>T variant is predicted to result in the amino acid substitution p.Thr343Ile. This variant has been reported in individuals with ovarian and endometrial cancer (Ramus et al. 2015. PubMed ID: 26315354; Table S2, Ring et al. 2016. PubMed ID: 27443514) as well as in an individual with colorectal adenocarcinoma that harbored a pathogenic variant in the FANCL gene (Table 7, Cabanillas et al. 2017. PubMed ID: 28717660). It is reported as a germline variant in a breast tumor and an ovarian tumor sample from the Cancer Genome Atlas (TCGA) database (Adamovich et al. 2019. PubMed ID: 30925164). However, it has also been reported in an unaffected individual (Table S4, Ramus et al. 2015. PubMed ID: 26315354). It has been reported in up to 0.04% of individuals from a large population database and has conflicting interpretations of likely benign and uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/127712/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.