ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.8324T>C (p.Met2775Thr) (rs80359073)

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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 RCV000130178 SCV000185015 uncertain significance Hereditary cancer-predisposing syndrome 2017-11-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Breast Cancer Information Core (BIC) (BRCA2) RCV000113902 SCV000147319 uncertain significance Breast-ovarian cancer, familial 2 2002-06-20 no assertion criteria provided clinical testing
Color RCV000130178 SCV000683954 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-16 criteria provided, single submitter clinical testing
Counsyl RCV000113902 SCV000785492 uncertain significance Breast-ovarian cancer, familial 2 2017-08-25 criteria provided, single submitter clinical testing
GeneDx RCV000213690 SCV000279340 uncertain significance not provided 2018-02-19 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.8324T>C at the cDNA level, p.Met2775Thr (M2775T) at the protein level, and results in the change of a Methionine to a Threonine (ATG>ACG). Using alternate nomenclature, this variant would be defined as BRCA2 8552T>C. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Met2775Thr was observed at an allele frequency of 0.03% (3/8734) in individuals of African ancestry in large population cohorts (Lek 2016). BRCA2 Met2775Thr 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 Met2775Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000045473 SCV000073486 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-05 criteria provided, single submitter clinical testing This sequence change replaces methionine with threonine at codon 2775 of the BRCA2 protein (p.Met2775Thr). The methionine residue is highly conserved and there is a moderate physicochemical difference between methionine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with a BRCA2-related disease. It has been observed in individuals in the Breast Cancer Information Core database (PMID: 10923033). ClinVar contains an entry for this variant (Variation ID: 52546). General algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD), and an algorithm developed specifically for the BRCA2 gene (PMID: 19043619), suggest that this missense change is likely to be tolerated. However, these predictions have 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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