ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.413G>T (p.Cys138Phe) (rs397507324)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129991 SCV000184815 uncertain significance Hereditary cancer-predisposing syndrome 2017-03-06 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000160017 SCV000210236 uncertain significance not provided 2018-01-11 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.413G>T at the cDNA level, p.Cys138Phe (C138F) at the protein level, and results in the change of a Cysteine to a Phenylalanine (TGT>TTT). Using alternate nomenclature, this variant would be defined as BRCA2 641G>T. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Cys138Phe was not observed in large population cohorts (Lek 2016). This variant is not located in a known functional domain. 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 Cys138Phe is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000779935 SCV000916876 uncertain significance not specified 2017-09-18 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.413G>T (p.Cys138Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant. The variant was not found in the control population dataset of ExAC in 115304 control chromosomes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS).
Invitae RCV000637505 SCV000758966 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-09-13 criteria provided, single submitter clinical testing This sequence change replaces cysteine with phenylalanine at codon 138 of the BRCA2 protein (p.Cys138Phe). The cysteine residue is weakly conserved and there is a large physicochemical difference between cysteine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 37882). 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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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) RCV000031463 SCV000054068 uncertain significance Breast-ovarian cancer, familial 2 2010-01-26 no assertion criteria provided clinical testing

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