ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.8824G>A (p.Ala2942Thr) (rs80359139)

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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 RCV000129548 SCV000184328 uncertain significance Hereditary cancer-predisposing syndrome 2018-02-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Breast Cancer Information Core (BIC) (BRCA2) RCV000114005 SCV000147468 uncertain significance Breast-ovarian cancer, familial 2 2003-12-23 no assertion criteria provided clinical testing
Color RCV000129548 SCV000906956 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-03 criteria provided, single submitter clinical testing
Counsyl RCV000114005 SCV000785244 uncertain significance Breast-ovarian cancer, familial 2 2017-06-13 criteria provided, single submitter clinical testing
GeneDx RCV000483549 SCV000571442 uncertain significance not provided 2018-04-30 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.8824G>A at the cDNA level, p.Ala2942Thr (A2942T) at the protein level, and results in the change of an Alanine to a Threonine (GCT>ACT). Using alternate nomenclature, this variant would be defined as BRCA2 9052G>A. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Ala2942Thr was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in 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 evidence, it is unclear whether BRCA2 Ala2942Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000045636 SCV000073649 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-10-30 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 2942 of the BRCA2 protein (p.Ala2942Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs80359139, ExAC 0.01%). This variant has been observed in an individual affected with endometrial cancer (PMID: 26689913). ClinVar contains an entry for this variant (Variation ID: 52687). An algorithm developed specifically for the BRCA2 gene suggests that this missense change is likely to be tolerated (PMID: 19043619). However, this prediction has not been confirmed by published functional studies and its 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.

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