ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.8299C>T (p.Pro2767Ser) (rs587782619)

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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 RCV000132002 SCV000187061 uncertain significance Hereditary cancer-predisposing syndrome 2017-07-10 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000587651 SCV000570333 uncertain significance not provided 2016-05-13 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.8299C>T at the cDNA level, p.Pro2767Ser (P2767S) at the protein level, and results in the change of a Proline to a Serine (CCT>TCT). Using alternate nomenclature, this variant would be defined as BRCA2 8527C>T. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Pro2767Ser 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 Proline and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Pro2767Ser occurs at a position that is conserved across species and is located in the SHFM1 binding domain (Marston 1999). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether BRCA2 Pro2767Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000587651 SCV000695140 uncertain significance not provided 2015-10-22 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.8299C>T affects a conserved nucleotide, resulting in amino acid change from Pro to Ser. 5/5 in-silico tools predict this variant to be damaging. This variant was not found in 120932 control chromosomes, and it has not been reported in affected individuals via peer reviewed publications (identified in a 28 y/o affected by sporadic breast fibrocystic dysplasia reported in a dissertation) nor evaluated for functional impact by in vivo/vitro studies. One reputable diagnostic lab classifies the variant as a VUS. Because of the absence of clinical information and the lack of functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available.

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