ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.796T>C (p.Phe266Leu) (rs587782433)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131491 SCV000186479 likely benign Hereditary cancer-predisposing syndrome 2018-04-02 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other strong data supporting benign classification,in silico models in agreement (benign)
Invitae RCV000555445 SCV000635622 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-05 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with leucine at codon 266 of the BRCA2 protein (p.Phe266Leu). The phenylalanine residue is weakly conserved and there is a small physicochemical difference between phenylalanine and leucine. This variant is present in population databases (rs587782433, ExAC 0.04%). This variant has been reported in individuals affected with breast cancer (PMID: 26543556, Invitae). However, in one of those individuals a pathogenic allele was also identified in BRCA1, which suggests that this c.796T>C variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 142396). 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.
Integrated Genetics/Laboratory Corporation of America RCV000590127 SCV000695110 uncertain significance not provided 2017-04-21 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.796T>C (p.Phe266Leu) variant involves the alteration of a non-conserved nucleotide and 4/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 5/118422 control chromosomes from ExAC, predominantly observed in the Latino subpopulation at a frequency of 0.000438 (5/11404), which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). The variant has also been reported in one Latino breast cancer patient, however without strong evidence for pathogenicity and the authors classify it as VUS (Dean_2015). One clinical diagnostic laboratory has classified this variant as likely benign, however without evidence to independently evaluate. One reputable database (UMD) has recently classified this variant as VUS and the database reports it in two individuals genotyped for BRCA1/2 genes without co-occurrence of a pathogenic BRCA1/2 variant. Therefore, until additional information becomes available (ie, clinical and functional studies), the variant of interest has been classified as a "Variant of Uncertain Significance (VUS)."
GeneDx RCV000610136 SCV000730713 likely benign not specified 2017-12-06 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Color RCV000131491 SCV000911745 likely benign Hereditary cancer-predisposing syndrome 2017-01-10 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000590127 SCV001133918 uncertain significance not provided 2019-01-23 criteria provided, single submitter clinical testing

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