ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.7940T>C (p.Leu2647Pro) (rs80359021)

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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 RCV000162550 SCV000212960 likely pathogenic Hereditary cancer-predisposing syndrome 2016-10-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other strong data supporting pathogenic classification,Deficient protein function in appropriate functional assay(s),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Rarity in general population databases (dbsnp, esp, 1000 genomes)
GeneDx RCV000486997 SCV000567765 likely pathogenic not provided 2017-02-10 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.7940T>C at the cDNA level, p.Leu2647Pro (L2647P) at the protein level, and results in the change of a Leucine to a Proline (CTA>CCA). Using alternate nomenclature, this variant has been previously published as BRCA2 8168T>C. This variant was strongly predicted by Lindor et al. (2012) to be likely pathogenic based on tumor pathology, clinical histories, family studies and co-occurrence with deleterious variants. In functional studies, BRCA2 Leu2647Pro displayed reduced homology-directed repair activity and was associated with centrosome and centriole amplification (Farrugia 2008, Guidugli 2013). BRCA2 Leu2647Pro 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 Leucine and Proline differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA2 Leu2647Pro occurs at a position that is conserved across species and is located within the DSS1 contacting residues of the DNA binding domain (Yang 2002). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on the currently available information, we consider BRCA2 Leu2647Pro to be a likely pathogenic variant.
Color RCV000162550 SCV000906945 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-29 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000083142 SCV000115216 uncertain significance Breast-ovarian cancer, familial 2 2010-09-30 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000083142 SCV000147223 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000083142 SCV000733308 likely pathogenic Breast-ovarian cancer, familial 2 no assertion criteria provided clinical testing

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