ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.8063T>C (p.Leu2688Pro) (rs80359045)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000219486 SCV000275420 likely pathogenic Hereditary cancer-predisposing syndrome 2017-01-31 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Deficient protein function in appropriate functional assay(s),Other data supporting pathogenic classification,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Good segregation with disease (lod 1.5-3 = 5-9 meioses)
Breast Cancer Information Core (BIC) (BRCA2) RCV000031719 SCV000147262 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Cancer Variant Interpretation Group UK,Institute of Cancer Research, London RCV000045408 SCV000897859 pathogenic Hereditary breast and ovarian cancer syndrome 2018-10-31 criteria provided, single submitter clinical testing Data used in classification. The variant was observed in 2 independent UK families undergoing clinical diagnostic testing of BRCA1/BRCA2 for HBOC, the denominator of which dataset of clinical testing was 16,600. Case control comparison against ethnically matched population data (2/16,600 in familial cases against 0/63,369 GNOMAD NFE controls) 2-sided Fishers exact: pexact= 0.043 (PS4). The variant is absent in the remainder of the GNOMAD populations (75,263 individuals). (PM2). Predicted deleterious on AlignGVGD, SIFT, Polyphen2 HumVar (PP3). Segregation demonstrated in one UK family, N<1/16 (PP1_mod). P>0.99 on HR assay as detailed in Guidugli et al 2012 (Couch laboratory), which has demonstrated full validation against genetic epidemiological data of clinical pathogicity (PS3). Classified as pathogenic by Ambry and Quest Diagnostics (PP5). Data not used in classification. An additional 2 families have been identified in the UK (not included in the previous dataset).There are 5 additional reports of this variant on ClinVar.
Color RCV000219486 SCV000906947 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-14 criteria provided, single submitter clinical testing
Invitae RCV000045408 SCV000073421 uncertain significance Hereditary breast and ovarian cancer syndrome 2017-06-15 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 2688 of the BRCA2 protein (p.Leu2688Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 38137). Experimental studies have shown that this missense change disrupts the homology-directed DNA break repair activity of BRCA2 (PMID: 24323938). Based on a multifactorial likelihood algorithm using genetic and in silico data, this variant has been determined to have a high probability of being pathogenic (PMID: 23108138). In addition, general algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD), and an algorithm developed specifically for the BRCA2 gene (PMID: 19043619), suggest that this missense change is likely deleterious. In summary, one in vitro assay shows that this variant disrupts protein function, and it is predicted to be deleterious by both a multifactorial and a gene-specific algorithm. However, this variant has not yet been shown to segregate with disease. For these reasons, this change has been classified as a Variant of Uncertain Significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000505844 SCV000296492 likely pathogenic not provided 2017-05-09 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031719 SCV000054326 uncertain significance Breast-ovarian cancer, familial 2 2006-08-15 no assertion criteria provided clinical testing

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