ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.7484T>C (p.Ile2495Thr) (rs80358974)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000162811 SCV000213292 uncertain significance Hereditary cancer-predisposing syndrome 2016-10-29 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Breast Cancer Information Core (BIC) (BRCA2) RCV000077402 SCV000147104 uncertain significance Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000478977 SCV000219396 uncertain significance Breast and/or ovarian cancer 2017-08-29 criteria provided, single submitter clinical testing
Color RCV000162811 SCV000911872 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-07 criteria provided, single submitter clinical testing
GeneDx RCV000657023 SCV000566623 uncertain significance not provided 2018-07-26 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.7484T>C at the cDNA level, p.Ile2495Thr (I2495T) at the protein level, and results in the change of an Isoleucine to a Threonine (ATT>ACT). Using alternate nomenclature, this variant would be defined as BRCA2 7712T>C. This variant has been observed in at least one individual with acute myeloid leukemia (Lu 2015). Functional studies by Mesman et al. (2018) demonstrated this variant to have 58% homology directed repair capacity and 84% Cisplatin sensitivity compared to wild-type in BRCA2-deficient mouse embryonic stem cells. BRCA2 Ile2495Thr was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the DNA binding domain and the FANCD2 binding domain (Yang 2002, UniProt). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA2 Ile2495Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000779955 SCV000916913 uncertain significance not specified 2018-03-26 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.7484T>C (p.Ile2495Thr) results in a non-conservative amino acid change located in the Breast cancer type 2 susceptibility protein, helical domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.1e-05 in 277204 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer (1.1e-05 vs 0.00075), allowing no conclusion about variant significance. c.7484T>C has been reported in the literature in an individual with AML (Lu_2014). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other pathogenic variant(s) have been reported (BRCA2 c.2545_2545delG, p.Val849Tyrfs), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance - possibly benign.
Invitae RCV000168601 SCV000073242 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-06-21 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 2495 of the BRCA2 protein (p.Ile2495Thr). The isoleucine residue is highly 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 individuals in the Breast Cancer Information Core database (PMID: 10923033). However, in one of these individuals a pathogenic allele was also identified in BRCA2, which suggests that this c.7484T>C variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 52342). 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 disruptive, 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.
Sharing Clinical Reports Project (SCRP) RCV000077402 SCV000109199 likely benign Breast-ovarian cancer, familial 2 2012-10-23 no assertion criteria provided clinical testing

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