ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.5885T>C (p.Ile1962Thr) (rs1060502377)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000457036 SCV000549483 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-11 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 1962 of the BRCA2 protein (p.Ile1962Thr). 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 been observed in two families affected with breast and/or ovarian cancer (PMID: 27062684, 30254663). ClinVar contains an entry for this variant (Variation ID: 409413). 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.
Genetic Services Laboratory, University of Chicago RCV000499719 SCV000593748 uncertain significance not specified 2017-02-02 criteria provided, single submitter clinical testing
Ambry Genetics RCV000564384 SCV000668584 likely benign Hereditary cancer-predisposing syndrome 2018-02-27 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other strong data supporting benign classification
Mendelics RCV000457036 SCV000838824 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000770729 SCV000902210 uncertain significance Breast and/or ovarian cancer 2017-06-08 criteria provided, single submitter clinical testing
Color RCV000564384 SCV000910249 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-21 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000499719 SCV000917030 uncertain significance not specified 2019-05-24 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.5885T>C (p.Ile1962Thr) 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 8e-06 in 250974 control chromosomes (gnomAD, exome dataset). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5885T>C has been reported in the literature in individuals affected with breast- or ovarian cancer (Zuntini_2018, Azzollini_2016). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrence with other pathogenic BRCA2 variant has been reported (c.8904delC, p.Val2969CysfsX7; in the UMD database), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six submitters have provided clinical-significance assessments for this variant in ClinVar after 2014 (without evidence for independent evaluation), and classified the variant as VUS (5x), likely benign (1x). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.

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