ClinVar Miner

Submissions for variant NM_000465.4(BARD1):c.1028C>T (p.Thr343Ile) (rs201032007)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000235113 SCV000149517 uncertain significance not provided 2018-01-04 criteria provided, single submitter clinical testing This variant is denoted BARD1 c.1028C>T at the cDNA level, p.Thr343Ile (T343I) at the protein level, and results in the change of a Threonine to an Isoleucine (ACC>ATC). This variant has been identified in individuals with endometrial, ovarian, and other cancer; however it was also observed in a healthy control (Ramus 2015, Ring 2016, Cabanillas 2017). BARD1 Thr343Ile was observed at an allele frequency of 0.04% (13/34,388) in individuals of Latino ancestry in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In-silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BARD1 Thr343Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115608 SCV000184446 uncertain significance Hereditary cancer-predisposing syndrome 2018-11-02 criteria provided, single submitter clinical testing The p.T343I variant (also known as c.1028C>T), located in coding exon 4 of the BARD1 gene, results from a C to T substitution at nucleotide position 1028. The threonine at codon 343 is replaced by isoleucine, an amino acid with similar properties. In one study, this variant was observed with a similar frequency in epithelial ovarian cancer cases (1/3236) and controls (1/3431) (Ramus SJ et al. J. Natl. Cancer Inst. 2015 Nov;107). This alteration was also identified in one individual from a cohort of 381 unselected endometrial cancer patients undergoing next generation-based panel testing (Ring KL et al. Mod. Pathol. 2016 Nov;29:1381-1389). In addition, in a study of paired somatic and germline testing, this alteration was identified in the germline of one individual with colorectal cancer (Cabanillas R et al. Mol. Genet. Genomic Med. 2017 Jul;5:336-359). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000206115 SCV000259877 uncertain significance Familial cancer of breast 2020-10-28 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 343 of the BARD1 protein (p.Thr343Ile). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is present in population databases (rs201032007, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in individuals affected with endometrial and ovarian cancer (PMID: 26315354, 27443514), as well as in an unaffected individual (PMID: 26315354). ClinVar contains an entry for this variant (Variation ID: 127712). This variant has been reported not to substantially affect BARD1 protein 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
PreventionGenetics,PreventionGenetics RCV000235113 SCV000806096 uncertain significance not provided 2016-12-16 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 Health, Inc RCV000115608 SCV000902712 likely benign Hereditary cancer-predisposing syndrome 2020-11-30 criteria provided, single submitter clinical testing

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