ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.2841G>T (p.Leu947Phe) (rs769971508)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000574394 SCV000661331 likely benign Hereditary cancer-predisposing syndrome 2016-07-11 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other strong data supporting benign classification
Integrated Genetics/Laboratory Corporation of America RCV000590404 SCV000694638 uncertain significance not provided 2017-08-24 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.2841G>T (p.Leu947Phe) variant involves the alteration of a non-conserved nucleotide and 4/5 in silico tools predict a benign outcome. However, these predictions have yet to be functionally assessed. This variant was found in 1/120660 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). A publication, Borg_2010, cites the variant in an affected individual with limited information (ie, lack of co-occurrence and cosegregation data). A clinical diagnostic laboratory classified this variant as uncertain significance. Taken together, this variant is classified as a "Variant of Uncertain Significance (VUS)," until additional information becomes available (ie, clinical and functional studies).
Invitae RCV000462471 SCV000549498 uncertain significance Hereditary breast and ovarian cancer syndrome 2016-12-19 criteria provided, single submitter clinical testing This sequence change replaces leucine with phenylalanine at codon 947 of the BRCA2 protein (p.Leu947Phe). The leucine residue is weakly conserved and there is a small physicochemical difference between leucine and phenylalanine. The frequency data for this variant (rs769971508) in the population databases is unreliable, as metrics indicate poor quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with a 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 phenylalanine 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. In summary, this variant is a novel missense change that is not predicted to affect 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.

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