ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.4862G>T (p.Cys1621Phe) (rs730881534)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000572608 SCV000661196 uncertain significance Hereditary cancer-predisposing syndrome 2017-01-17 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence,In silico models in agreement (benign)
GeneDx RCV000160080 SCV000210342 uncertain significance not provided 2016-11-14 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.4862G>T at the cDNA level, p.Cys1621Phe (C1621F) at the protein level, and results in the change of a Cysteine to a Phenylalanine (TGT>TTT). Using alternate nomenclature this variant would be defined as BRCA2 5090G>T. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Cys1621Phe was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Cysteine and Phenylalanine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Cys1621Phe occurs at a position that is not conserved and is located in the RAD51 and POLH binding domains (Roy 2012, Buisson 2014). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether BRCA2 Cys1621Phe is pathogenic or benign. We consider it to be a variant of uncertain significance.

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