ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.3422C>T (p.Thr1141Ile) (rs397507308)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color RCV000579950 SCV000683556 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-04 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000781057 SCV000918848 uncertain significance not specified 2018-06-01 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.3422C>T (p.Thr1141Ile) results in a non-conservative amino acid change located in the BRCA2 repeat region, between the first and second repeat (IPR002093) of 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 4.1e-06 in 245788 control chromosomes. 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.3422C>T in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both of them classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV000200443 SCV000254182 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-25 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 1141 of the BRCA2 protein (p.Thr1141Ile). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and isoleucine. 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: 37839). 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 isoleucine 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.
Sharing Clinical Reports Project (SCRP) RCV000031420 SCV000054025 uncertain significance Breast-ovarian cancer, familial 2 2008-06-19 no assertion criteria provided clinical testing

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