ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.10240A>G (p.Thr3414Ala) (rs80358405)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129127 SCV000183845 uncertain significance Hereditary cancer-predisposing syndrome 2017-05-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Seen in trans with a mutation or in homozygous state in individual without severe disease for that gene
GeneDx RCV000160262 SCV000210701 likely benign not specified 2017-09-20 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Counsyl RCV000077652 SCV000489448 uncertain significance Breast-ovarian cancer, familial 2 2016-10-11 criteria provided, single submitter clinical testing
Invitae RCV000458506 SCV000549766 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-07 criteria provided, single submitter clinical testing This sequence change replaces threonine with alanine at codon 3414 of the BRCA2 protein (p.Thr3414Ala). The threonine residue is weakly conserved and there is a small physicochemical difference between threonine and alanine. This variant is present in population databases (rs80358405, ExAC 0.003%). This variant has been reported in families affected with breast and/or ovarian cancer (PMID: 27211102, 24372583). ClinVar contains an entry for this variant (Variation ID: 91744). 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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 RCV000129127 SCV000903280 benign Hereditary cancer-predisposing syndrome 2017-06-27 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000160262 SCV000916836 uncertain significance not specified 2018-02-05 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.10240A>G (p.Thr3414Ala) results in a non-conservative amino acid change in 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 2.9e-05 in 276468 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer (2.9e-05 vs 0.00075), allowing no conclusion about variant significance. c.10240A>G has been reported in the literature in affected individuals. These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple clinical diagnostic laboratories/databases have classified this variant as VUS, and two labs/databases classified it as Likely benign, all without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000985459 SCV001133668 likely benign not provided 2019-08-19 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000077652 SCV000109455 likely benign Breast-ovarian cancer, familial 2 2007-07-09 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000077652 SCV000145771 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing

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