ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.4849A>C (p.Ser1617Arg) (rs80358707)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000165988 SCV000216746 uncertain significance Hereditary cancer-predisposing syndrome 2014-09-15 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Breast Cancer Information Core (BIC) (BRCA2) RCV000113351 SCV000146493 uncertain significance Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing
Counsyl RCV000113351 SCV000786045 uncertain significance Breast-ovarian cancer, familial 2 2018-02-23 criteria provided, single submitter clinical testing
GeneDx RCV000484473 SCV000570558 uncertain significance not provided 2018-08-06 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.4849A>C at the cDNA level, p.Ser1617Arg (S1617R) at the protein level, and results in the change of a Serine to an Arginine (AGT>CGT). Using alternate nomenclature, this variant would be defined as BRCA2 5077A>C. This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. BRCA2 Ser1617Arg was not observed in large population cohorts (Lek 2016). This variant is located in the RAD51 and POLH binding domains (Roy 2012, Buisson 2014). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether BRCA2 Ser1617Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000780022 SCV000917022 uncertain significance not specified 2018-09-17 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.4849A>C (p.Ser1617Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 245512 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.4849A>C in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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