ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.620C>T (p.Thr207Ile) (rs41293471)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000165697 SCV000216436 uncertain significance Hereditary cancer-predisposing syndrome 2017-10-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000165697 SCV000911793 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-18 criteria provided, single submitter clinical testing
GeneDx RCV000759634 SCV000279426 uncertain significance not provided 2018-08-24 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.620C>T at the cDNA level, p.Thr207Ile (T207I) at the protein level, and results in the change of a Threonine to an Isoleucine (ACT>ATT). Using alternate nomenclature, this variant would be defined as BRCA2 848C>T. BRCA2 Thr207Ile was identified in at least one individual each with breast cancer, nonmucinous ovarian carcinoma, and colorectal cancer (Alsop 2012, Lu 2015, Pearlman 2017). Multiple in silico splicing models predict this variant may increase use of a cryptic splice acceptor site, and a minigene assay by Di Giacomo et al. (2013) demonstrated that BRCA2 c.620C>T leads to partial exon 7 skipping, producing both full-length and truncated mRNA transcripts. Exon 7 skipping has been reported to create a frameshift ultimately causing a premature nonsense codon, resulting in a product that appears to undergo nonsense-mediated mRNA decay (Pyne 2000). BRCA2 Thr207Ile was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. Protein-based 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 BRCA2 Thr207Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000214941 SCV000916908 uncertain significance not specified 2018-03-23 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.620C>T (p.Thr207Ile) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. Two publications report experimental evidence that this missense variant affects mRNA splicing (~42-45% normal transcription products)(DiGiacomo_2013, Soukarieh_2016). The variant allele was found at a frequency of 1.6e-05 in 246108 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer (1.6e-05 vs 7.50e-04), allowing no conclusion about variant significance. c.620C>T has been reported in the literature in individuals affected with Breast, Ovarian, and Colon Cancer (Alsop_2012, Tung_2014, Lu_2015) . These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Invitae RCV000461512 SCV000549716 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-11-08 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 207 of the BRCA2 protein (p.Thr207Ile). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is present in population databases (rs41293471, ExAC <0.01%). This variant has been observed in individuals affected with breast, ovarian or colorectal cancer (PMID: 26689913, 22711857, 27978560). ClinVar contains an entry for this variant (Variation ID: 186155). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. In an experimental study, this variant was reported to cause an mRNA splicing defect resulting in increased skipping of exon 7 (PMID: 23983145). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000214941 SCV000600684 uncertain significance not specified 2016-10-10 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759634 SCV000889089 uncertain significance not provided 2018-01-03 criteria provided, single submitter clinical testing

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