ClinVar Miner

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

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130329 SCV000185179 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-26 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Breast Cancer Information Core (BIC) (BRCA2) RCV000077458 SCV000147518 uncertain significance Breast-ovarian cancer, familial 2 2003-12-23 no assertion criteria provided clinical testing
Color RCV000130329 SCV000689171 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-09 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
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
Invitae RCV000045694 SCV000073707 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-06-15 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 3011 of the BRCA2 protein (p.Leu3011Pro). 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 observed in individuals with hereditary breast and ovarian cancer (PMID: 27376475, 10923033). However, in one of these individuals a pathogenic allele was also identified in BRCA1, which suggests that this c.9032T>C variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 52732). Experimental study has shown that this change produces an intermediate homologous repair activity compared to the wild-type BRCA2 protein (PMID: 29394989). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of 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

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