ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.6760T>C (p.Phe2254Leu) (rs1555284847)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000590351 SCV000694993 uncertain significance not provided 2016-05-09 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.6760T>C (p.Phe2254Leu) variant involves the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a benign outcome (SNPs&GO not captured due to low reliability index). This variant is absent in 121018 control chromosomes. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; 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 was classified as a variant of uncertain significance (VUS) until additional information becomes available.
Invitae RCV000701143 SCV000829927 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-02-16 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with leucine at codon 2254 of the BRCA2 protein (p.Phe2254Leu). The phenylalanine residue is moderately conserved and there is a small physicochemical difference between phenylalanine and leucine. 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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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