ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.5885T>C (p.Ile1962Thr) (rs1060502377)

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Total submissions: 8
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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 2020-09-19 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 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 Health, Inc RCV000564384 SCV000910249 uncertain significance Hereditary cancer-predisposing syndrome 2021-01-20 criteria provided, single submitter clinical testing This missense variant replaces isoleucine with threonine at codon 1962 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in families affected with hereditary breast and/or ovarian cancer in the literature (PMID: 27062684, 29684080, 30254663, 31409081, 32438681). This variant has been identified in 3/282368 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000499719 SCV000917030 uncertain significance not specified 2020-08-25 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). 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 and/or ovarian cancer (Zuntini_2018, Azzollini_2016, Machackova_2019, Santonocito_2020). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. One co-occurrence with another pathogenic variant has been reported (BRCA2 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. Seven ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (6x) and likely benign (1x). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Mendelics RCV000989045 SCV001139130 uncertain significance Breast-ovarian cancer, familial 2 2019-05-28 criteria provided, single submitter clinical testing

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