ClinVar Miner

Submissions for variant NM_001128425.1(MUTYH):c.1000C>G (p.Pro334Ala) (rs587778537)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000162642 SCV000213079 uncertain significance Hereditary cancer-predisposing syndrome 2018-11-29 criteria provided, single submitter clinical testing The p.P334A variant (also known as c.1000C>G), located in coding exon 12 of the MUTYH gene, results from a C to G substitution at nucleotide position 1000. The proline at codon 334 is replaced by alanine, an amino acid with highly similar properties. This alteration has previously been detected in an individual with greater than 10 colon polyps (Guarinos C, Clin. Cancer Res. 2014 Mar; 20(5):1158-68). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000476756 SCV000545705 uncertain significance MYH-associated polyposis 2020-10-16 criteria provided, single submitter clinical testing This sequence change replaces proline with alanine at codon 334 of the MUTYH protein (p.Pro334Ala). The proline residue is weakly conserved and there is a small physicochemical difference between proline and alanine. This variant is present in population databases (rs587778537, ExAC 0.002%). This variant has been reported in an individual with multiple adenomatous and serrated polyps (PMID: 24470512). ClinVar contains an entry for this variant (Variation ID: 183823). 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.
Fulgent Genetics,Fulgent Genetics RCV000765174 SCV000896407 uncertain significance MYH-associated polyposis; Pilomatrixoma; Neoplasm of stomach 2018-10-31 criteria provided, single submitter clinical testing
Color Health, Inc RCV000162642 SCV000903809 uncertain significance Hereditary cancer-predisposing syndrome 2019-06-30 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000780497 SCV000917801 uncertain significance not specified 2018-03-30 criteria provided, single submitter clinical testing Variant summary: MUTYH c.1000C>G (p.Pro334Ala) results in a non-conservative amino acid change in the encoded protein sequence that lies 3 nucleotides away from an exon-intron junction. Four of five in-silico tools predict a benign effect of the variant on protein function. 4/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.3e-05 in 224868 control chromosomes. This frequency is not higher than expected for a pathogenic variant in MUTYH causing MUTYH-associated Polyposis (1.3e-05 vs 0.0046), allowing no conclusion about variant significance. c.1000C>G has been reported in the literature in individuals affected with MUTYH-associated Polyposis. However, these reports do not provide unequivocal conclusions about an association of the variant with MUTYH-associated Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and both classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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