ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.3005A>C (p.Asn1002Thr) (rs730881518)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000219400 SCV000275311 uncertain significance Hereditary cancer-predisposing syndrome 2017-02-10 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000160054 SCV000210301 uncertain significance not provided 2017-12-18 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.3005A>C at the cDNA level, p.Asn1002Thr (N1002T) at the protein level, and results in the change of an Asparagine to a Threonine (AAT>ACT). Using alternate nomenclature, this variant would be defined as BRCA2 3233A>C. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Asn1002Thr was not observed in large population cohorts (Lek 2016). Since Asparagine and Threonine share similar properties, this is considered a conservative amino acid substitution. BRCA2 Asn1002Thr is located in BRC1 repeat (Cole 2011). In-silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether BRCA2 Asn1002Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000225786 SCV000283200 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-11-16 criteria provided, single submitter clinical testing This sequence change replaces asparagine with threonine at codon 1002 of the BRCA2 protein (p.Asn1002Thr). The asparagine residue is weakly conserved and there is a small physicochemical difference between asparagine 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 BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 182193). 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 tolerated, 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.

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