ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.8807T>C (p.Leu2936Ser) (rs398122714)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000132403 SCV000187495 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-31 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000587247 SCV000210485 uncertain significance not provided 2019-01-03 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.8807T>C at the cDNA level, p.Leu2936Ser (L2936S) at the protein level, and results in the change of a Leucine to a Serine (TTG>TCG). Using alternate nomenclature, this variant would be defined as BRCA2 9035T>C. This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. BRCA2 Leu2936Ser was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant 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 Leu2936Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000587247 SCV000227873 uncertain significance not provided 2014-08-11 criteria provided, single submitter clinical testing
Invitae RCV000198146 SCV000254221 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-10-19 criteria provided, single submitter clinical testing This sequence change replaces leucine with serine at codon 2936 of the BRCA2 protein (p.Leu2936Ser). The leucine residue is moderately conserved and there is a large physicochemical difference between leucine and serine. This variant is present in population databases (rs398122714, ExAC 0.01%) but has not been reported in the literature in individuals with a BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 91735). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Institute for Biomarker Research,Medical Diagnostic Laboratories, L.L.C. RCV000198146 SCV000267848 uncertain significance Hereditary breast and ovarian cancer syndrome 2016-04-25 criteria provided, single submitter clinical testing
Counsyl RCV000077643 SCV000488314 uncertain significance Breast-ovarian cancer, familial 2 2016-02-24 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000160158 SCV000600826 uncertain significance not specified 2016-12-16 criteria provided, single submitter clinical testing
Color RCV000132403 SCV000683999 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000587247 SCV000695183 uncertain significance not provided 2016-09-01 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.8807T>C (p.Leu2936Ser) variant involves the alteration of a conserved nucleotide. Leu2936 is not conserved across species and is not located in a known functional domain. 5/5 in silico tools predict a damaging outcome for this variant, however these predictions have not been confirmed with functional studies. This variant was found in 2/120590 control chromosomes at a frequency of 0.0000166, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). The variant of interest has not, to our knowledge, been reported in affected individuals via publications. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000587247 SCV000889168 uncertain significance not provided 2018-02-18 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000077643 SCV000109446 likely benign Breast-ovarian cancer, familial 2 2012-09-19 no assertion criteria provided clinical testing

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