ClinVar Miner

Submissions for variant NM_001048171.1(MUTYH):c.1076C>T (p.Ala359Val) (rs35352891)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000123139 SCV000166441 likely benign MYH-associated polyposis 2020-12-03 criteria provided, single submitter clinical testing
GeneDx RCV000417387 SCV000211422 likely benign not specified 2018-01-20 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.
Ambry Genetics RCV000160763 SCV000214342 likely benign Hereditary cancer-predisposing syndrome 2018-06-11 criteria provided, single submitter clinical testing In silico models in agreement (benign) ;Intact protein function observed by in vitro/ex vivo assays;Seen in conjunction with two deleterious mutations confirmed in trans in symptomatic individuals;Sub-population frequency in support of benign classification (not ava blue, manual h-w)
Counsyl RCV000123139 SCV000487369 likely benign MYH-associated polyposis 2016-07-18 criteria provided, single submitter clinical testing
Institute for Biomarker Research,Medical Diagnostic Laboratories, L.L.C. RCV000160763 SCV000576449 uncertain significance Hereditary cancer-predisposing syndrome 2017-02-14 criteria provided, single submitter clinical testing
Color Health, Inc RCV000160763 SCV000685541 benign Hereditary cancer-predisposing syndrome 2016-03-21 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000417387 SCV000917803 likely benign not specified 2020-11-06 criteria provided, single submitter clinical testing Variant summary: MUTYH c.1118C>T (p.Ala373Val) results in a non-conservative amino acid change located in the MutY, C-terminal domain (IPR029119) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0004 in 250664 control chromosomes, predominantly at a frequency of 0.0046 within the East Asian subpopulation in the gnomAD database. The frequency within the East Asian subpopulation is equal to the estimated maximal expected allele frequency for a pathogenic variant in MUTYH causing MUTYH-Associated Polyposis (0.0046). In addition, the variant was found at an even higher frequency of 0.0091 in Japanese controls in the HGVD-Kyoto database, suggesting that this variant is a benign polymorphism found primarily in individuals of East Asian ethnicity. c.1118C>T has been reported in affected individuals in the literature, including at least one occurrence in an individual presenting with colorectal polyposis, who was homozygous for both the variant of interest, but also the likely pathogenic variant p.G272E (Yanaru-Fujisawa_2008). Cosegregation studies associating the variant of interest with disease have not, to our knowledge, been performed. The reports in patients in the literature do not provide unequivocal conclusions about association of the variant with MUTYH-Associated Polyposis. At least two publications report experimental evidence indicating that the variant does not significantly affect DNA-glycosylase activity (e.g. Goto_2010, Yanaru-Fujisawa_2008). Ten other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (benign/likely benign, n=7; uncertain significance, n=2; pathogenic, n=1). Based on the evidence outlined above, the variant was classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000034668 SCV001134465 likely benign not provided 2019-01-25 criteria provided, single submitter clinical testing
Mendelics RCV000123139 SCV001135253 likely benign MYH-associated polyposis 2019-05-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000123139 SCV001255468 uncertain significance MYH-associated polyposis 2018-10-26 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000034668 SCV001500818 uncertain significance not provided 2020-10-01 criteria provided, single submitter clinical testing
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034668 SCV000043371 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.
GeneReviews RCV000123139 SCV000246165 pathogenic MYH-associated polyposis 2019-10-08 no assertion criteria provided literature only
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000123139 SCV000592708 likely benign MYH-associated polyposis no assertion criteria provided clinical testing The MUTYH p.Ala373Val variant was identified in 4 of 256 proband chromosomes (frequency: 0.016) from Japanese or Korean individuals or families with adenomatous polyposis, and was identified in 4 of 192 control chromosomes (frequency: 0.021) from healthy individuals (Kim 2007; Yanaru-Fujisawa 2008); however, an insufficient number of controls were included in these studies to determine the frequency of this variant in the general population. Functional studies assessing glycosylase activity of the MUTYH protein showed that the p.Ala373Val variant retained its activity (Goto 2010, Yanaru-Fujisawa 2008). The variant was also identified in dbSNP (rs35352891) “With allele of uncertain significance”, with a minor allele frequency of 0.001(1000 Genomes Project), HGMD, and the ClinVar database (as a variant of unknown significance). The p.Ala373 residue is conserved in mammals; however, computational analyses (PolyPhen-2, SIFT, AlignGVGD, MutationTaster) provide inconsistent predictions regarding the impact to the protein and this information is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as predicted benign.

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