ClinVar Miner

Submissions for variant NM_001048174.2(MUTYH):c.1174C>G (p.Leu392Val) (rs144079536)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000205972 SCV000261889 uncertain significance MYH-associated polyposis 2020-10-09 criteria provided, single submitter clinical testing This sequence change replaces leucine with valine at codon 420 of the MUTYH protein (p.Leu420Val). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in an individual affected with breast cancer (PMID: 28202063). ClinVar contains an entry for this variant (Variation ID: 220923). 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 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.
Counsyl RCV000205972 SCV000487367 uncertain significance MYH-associated polyposis 2016-06-23 criteria provided, single submitter clinical testing
Ambry Genetics RCV000563480 SCV000662597 uncertain significance Hereditary cancer-predisposing syndrome 2020-03-04 criteria provided, single submitter clinical testing The p.L420V variant (also known as c.1258C>G), located in coding exon 13 of the MUTYH gene, results from a C to G substitution at nucleotide position 1258. The leucine at codon 420 is replaced by valine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Health, Inc RCV000563480 SCV000685558 uncertain significance Hereditary cancer-predisposing syndrome 2020-01-24 criteria provided, single submitter clinical testing
Mendelics RCV000205972 SCV000837749 uncertain significance MYH-associated polyposis 2018-07-02 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001201302 SCV001372439 uncertain significance not specified 2020-06-16 criteria provided, single submitter clinical testing Variant summary: MUTYH c.1258C>G (p.Leu420Val) results in a conservative amino acid change located in the NUDIX hydrolase domain (IPR000086) / MutY, C-terminal (IPR029119) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251166 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1258C>G has been reported in the literature in individuals affected with breast cancer (Jalkh_2017). This report, however does not provide unequivocal conclusions about association of the variant with MUTYH-Associated Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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