ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.7985C>T (p.Thr2662Met) (rs431825362)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000163213 SCV000213736 likely benign Hereditary cancer-predisposing syndrome 2017-03-02 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other strong data supporting benign classification,In silico models in agreement (benign)
Color RCV000163213 SCV000903146 likely benign Hereditary cancer-predisposing syndrome 2017-04-20 criteria provided, single submitter clinical testing
GeneDx RCV000588790 SCV000279209 uncertain significance not provided 2018-10-17 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.7985C>T at the cDNA level, p.Thr2662Met (T2662M) at the protein level, and results in the change of a Threonine to a Methionine (ACG>ATG). Using alternate nomenclature, this variant would be defined as BRCA2 8213C>T. In a minigene assay, BRCA2 Thr2662Met was shown to result in 3.3% of transcripts skipping exon 18, a naturally occurring isoform (Fraile-Bethencourt 2017). BRCA2 Thr2662Met was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located within the DNA binding domain (Yang 2002). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available information, it is unclear whether BRCA2 Thr2662Met is pathogenic or benign. We consider it to be a variant of uncertain significance.
GeneKor MSA RCV000163213 SCV000821947 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000588790 SCV000695115 uncertain significance not provided 2016-04-04 criteria provided, single submitter clinical testing Variant Summary: The variant of interest causes a missense change involving a conserved nucleotide with 3/4 in silico programs (SNPs&GO not captured here due to low reliability index) predict a "benign" outcome, although these predictions have yet to be functionally assessed. The variant of interest was not observed in controls (ExAC, 1000 Gs or ESP), nor has it been, to our knowledge, reported in affected individuals via publications. A reputable clinical laboratory and database cites the variant as "uncertain significance." Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as a "Variant of Uncertain Significance (VUS)," until additional information becomes available.
Invitae RCV000465103 SCV000549530 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-05-04 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 2662 of the BRCA2 protein (p.Thr2662Met). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 184089). 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 methionine 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. 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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