ClinVar Miner

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

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000045408 SCV000073421 likely pathogenic Hereditary breast and ovarian cancer syndrome 2020-10-08 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). This variant has been reported in individuals in the Breast Cancer Information Core database (PMID: 10923033). ClinVar contains an entry for this variant (Variation ID: 38137). This variant has been reported to affect BRCA2 protein function (PMID: 23108138, 24323938, 29394989, 30696104). Based on a multifactorial likelihood algorithm using genetic, in silico, and statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 23108138). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics RCV000219486 SCV000275420 pathogenic Hereditary cancer-predisposing syndrome 2020-01-22 criteria provided, single submitter clinical testing The p.L2688P pathogenic mutation (also known as c.8063T>C), located in coding exon 17 of the BRCA2 gene, results from a T to C substitution at nucleotide position 8063. The leucine at codon 2688 is replaced by proline, an amino acid with similar properties. In one study utilizing a bioinformatics method that integrates information about protein sequence, conservation, and structure in a protein likelihood ratio, the effect of this alteration was predicted deleterious (Karchin R et al. Cancer Inform. 2008 Apr;6:203-16). This alteration has been predicted to be pathogenic using homology-directed DNA repair (HDR) functional assays (Guidugli L et al. Cancer Res. 2013 Jan;73:265-75; Guidugli L et al. Am. J. Hum. Genet. 2018 02;102:233-248; Hart SN et al. Genet. Med. 2019 01;21:71-80). This variant segregated with disease in multiple families (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000505844 SCV000296492 likely pathogenic not provided 2017-05-09 criteria provided, single submitter 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 Health, Inc RCV000219486 SCV000906947 likely pathogenic Hereditary cancer-predisposing syndrome 2019-10-08 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000045408 SCV001372328 likely pathogenic Hereditary breast and ovarian cancer syndrome 2020-06-29 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.8063T>C (p.Leu2688Pro) results in a non-conservative amino acid change located in the BRCA2, OB1 domain (IPR015187) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251256 control chromosomes. c.8063T>C has been reported in the literature in individuals from at-least one family affected with Hereditary Breast And Ovarian Cancer although the exact number of case counts have not been specified (example, Guidugli_2013). These data do not allow any conclusion about variant significance. Several publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a loss of ability of BRCA2 to interact with the small (70-residues) DSS1 peptide, which appears to be crucial for the maintenance of its stability and correct conformation for the repair of DNA double stranded breaks (DSB's) by homologous recombination (HR) and the formation of DNA damage induced RAD51 foci (Caleca_2019). Consistently, other studies report a corresponding loss of HDR activity (example, Guidugli_2013 and Hart_2019). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=1)/likely pathogenic (n=4). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Sharing Clinical Reports Project (SCRP) RCV000031719 SCV000054326 uncertain significance Breast-ovarian cancer, familial 2 2006-08-15 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031719 SCV000147262 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing

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