ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.5171T>C (p.Ile1724Thr) (rs80358743)

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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 RCV000131403 SCV000186379 likely benign Hereditary cancer-predisposing syndrome 2018-01-17 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Co-occurence with mutation in same gene (phase unknown)
Breast Cancer Information Core (BIC) (BRCA2) RCV000113393 SCV000146557 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Color RCV000131403 SCV000903516 likely benign Hereditary cancer-predisposing syndrome 2018-06-13 criteria provided, single submitter clinical testing
Counsyl RCV000113393 SCV000488145 uncertain significance Breast-ovarian cancer, familial 2 2016-02-19 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000074534 SCV000591948 likely benign not specified 2012-03-15 criteria provided, single submitter clinical testing
GeneDx RCV000074534 SCV000108619 likely benign not specified 2017-01-30 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.
Integrated Genetics/Laboratory Corporation of America RCV000074534 SCV000918852 uncertain significance not specified 2018-03-07 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.5171T>C (p.Ile1724Thr) 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. However, these predictions have yet to be functionally assessed. The variant was absent in 269160 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.5171T>C in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant with conflicting classifications "uncertain significance" or "likely benign." Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV000044591 SCV000072604 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-27 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 1724 of the BRCA2 protein (p.Ile1724Thr). The isoleucine residue is weakly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 51803). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000113393 SCV000296509 uncertain significance Breast-ovarian cancer, familial 2 2016-06-04 criteria provided, single submitter clinical testing

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