ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.1232T>C (p.Ile411Thr) (rs79597821)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129491 SCV000184263 likely benign Hereditary cancer-predisposing syndrome 2016-01-19 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other strong data supporting benign classification
Color Health, Inc RCV000129491 SCV000906021 uncertain significance Hereditary cancer-predisposing syndrome 2020-01-21 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001174663 SCV001337880 uncertain significance not specified 2020-01-06 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.1232T>C (p.Ile411Thr) 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 5.1e-05 in 272756 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer (5.1e-05 vs 0.00075), allowing no conclusion about variant significance. c.1232T>C has been reported in the literature in individuals affected with Breast Cancer (Capanu_2011, Momozawa_2018). However, the frequency of this variant in a large Japanese breast cancer patient cohort is similar to the frequency in controls, suggesting this variant is unlikely to be pathogenic (Momozawa_2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely benign, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Invitae RCV001343210 SCV001537174 uncertain significance Hereditary breast and ovarian cancer syndrome 2020-05-11 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 411 of the BRCA2 protein (p.Ile411Thr). The isoleucine residue is weakly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs79597821, ExAC 0.01%). This variant has been observed in individual(s) with breast cancer as well as in unaffected individuals (PMID: 20104584, 30287823). This variant is also known as c.1460T>C in the literature. ClinVar contains an entry for this variant (Variation ID: 141125). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: Tolerated; PolyPhen-2: Benign; Align-GVGD: Class C0. The threonine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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.

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