ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.4412G>T (p.Arg1471Ile) (rs786203839)

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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 RCV000167319 SCV000218169 uncertain significance Hereditary cancer-predisposing syndrome 2017-10-11 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Invitae RCV000461661 SCV000549806 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-01-10 criteria provided, single submitter clinical testing This sequence change replaces arginine with isoleucine at codon 1471 of the BRCA2 protein (p.Arg1471Ile). The arginine residue is weakly conserved and there is a moderate physicochemical difference between arginine and isoleucine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 187579). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare 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.
Integrated Genetics/Laboratory Corporation of America RCV000590203 SCV000694772 uncertain significance not provided 2017-05-08 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.4412G>T (p.Arg1471Ile) variant involves the alteration of a non-conserved nucleotide and 3/5 in silico tools predict a benign outcome. However, these predictions have yet to be functionally assessed. This variant was found in 3/119376 control chromosomes at a frequency of 0.0000251, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). An internal LCA sample reports the variant to co-occur with a pathogenic BRCA2 variant, c.8414_8416delinsC (p.Leu2805fsX6 - classified as pathogenic by LCA). Multiple clinical diagnostic laboratories classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a "Variant of Uncertain Significance - Possibly Benign" until additional information becomes available.

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