ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.8420C>T (p.Ser2807Leu) (rs55763607)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000045513 SCV000073526 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-21 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 2807 of the BRCA2 protein (p.Ser2807Leu). The serine residue is highly conserved and there is a large physicochemical difference between serine and leucine. This variant is present in population databases (rs55763607, ExAC 0.03%). This variant has not been reported in the literature in individuals with BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 52582). Experimental studies have shown that this missense change behaves similarly to the wild-type protein in a homology-directed repair assay (PMID: 23108138). 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.
Ambry Genetics RCV000130247 SCV000185091 uncertain significance Hereditary cancer-predisposing syndrome 2017-07-21 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000588703 SCV000210471 uncertain significance not provided 2017-12-18 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.8420C>T at the cDNA level, p.Ser2807Leu (S2807L) at the protein level, and results in the change of a Serine to a Leucine (TCG>TTG). Using alternate nomenclature, this variant would be defined as BRCA2 8648C>T. This variant was predicted to be of uncertain clinical significance by a multifactorial likelihood model and homology-directed DNA break repair functional assay (Guidugli 2013). BRCA2 Ser2807Leu was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Serine and Leucine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Ser2807Leu is located in the DSS1 contacting residue within 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 Ser2807Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl RCV000083147 SCV000487929 uncertain significance Breast-ovarian cancer, familial 2 2015-12-04 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000212274 SCV000592189 uncertain significance not specified 2015-08-27 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212274 SCV000600803 uncertain significance not specified 2016-09-09 criteria provided, single submitter clinical testing
Color RCV000130247 SCV000689123 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-25 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000588703 SCV000695152 uncertain significance not provided 2016-06-13 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.8420C>T (p.Ser2807Leu) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 3/121394 control chromosomes at a frequency of 0.0000247, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). One functional study has reported the variant to be classified as nonpathogenic via HDR assay (Guidugli_2012). However the variant has not been reported in affected individuals in the litature. Multiple clinical diagnostic laboratories/reputable databases classified this variant as VUS. Because of the absence of clinical information and the lack of functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available.
Institute for Biomarker Research,Medical Diagnostic Laboratories, L.L.C. RCV000130247 SCV000803160 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-23 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000588703 SCV000887940 uncertain significance not provided 2018-05-30 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000083147 SCV000115221 uncertain significance Breast-ovarian cancer, familial 2 2012-05-01 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000083147 SCV000147359 uncertain significance Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing

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