ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.9032T>C (p.Leu3011Pro) (rs80359155)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000045694 SCV000073707 likely benign Hereditary breast and ovarian cancer syndrome 2019-12-19 criteria provided, single submitter clinical testing
Ambry Genetics RCV000130329 SCV000185179 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-22 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
GeneDx RCV000505780 SCV000210678 uncertain significance not provided 2018-07-25 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.9032T>C at the cDNA level, p.Leu3011Pro (L3011P) at the protein level, and results in the change of a Leucine to a Proline (CTT>CCT). Using alternate nomenclature, this variant would be defined as BRCA2 9260T>C. This variant has been observed in at least one individual with hereditary breast and/or ovarian cancer and has been reported to co-occur with a pathogenic variant in BRCA1 (Szabo 2000, Schenkel 2016). BRCA2 Leu3011Pro exhibited an intermediate level of homology-directed repair (HDR) activity in a cell-based functional assay (Guidugli 2018). BRCA2 Leu3011Pro was not observed in large population cohorts (Lek 2016). BRCA2 Leu3011Pro is located in the DNA binding domain (Yang 2002). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA2 Leu3011Pro is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Illumina Clinical Services Laboratory,Illumina RCV000377237 SCV000383797 uncertain significance Fanconi anemia 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000045694 SCV000383798 uncertain significance Hereditary breast and ovarian cancer syndrome 2016-06-14 criteria provided, single submitter clinical testing
Color RCV000130329 SCV000689171 uncertain significance Hereditary cancer-predisposing syndrome 2019-08-16 criteria provided, single submitter clinical testing
Counsyl RCV000077458 SCV000784836 uncertain significance Breast-ovarian cancer, familial 2 2016-12-23 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001175463 SCV001339038 uncertain significance not specified 2020-03-09 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.9032T>C (p.Leu3011Pro) results in a non-conservative amino acid change in 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 250554 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.9032T>C has been reported in the literature in at least one individual evaluated for Hereditary Breast and Ovarian Cancer (Schenkel_2016). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrence with another pathogenic variant has been reported (BRCA1 c.66_67insA, p.Leu22_Glu23?fs; BIC database), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in an intermediate level (approximately 40%) of normal homology-directed repair activity (Guidugli_2018). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Sharing Clinical Reports Project (SCRP) RCV000077458 SCV000109256 likely benign Breast-ovarian cancer, familial 2 2012-08-03 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000077458 SCV000147518 uncertain significance Breast-ovarian cancer, familial 2 2003-12-23 no assertion criteria provided clinical testing

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