ClinVar Miner

Submissions for variant NM_001048171.1(MUTYH):c.1213G>A (p.Ala405Thr) (rs587780744)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000123142 SCV000166445 uncertain significance MYH-associated polyposis 2020-10-26 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 419 of the MUTYH protein (p.Ala419Thr). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs587780744, ExAC 0.009%). This variant has been reported in an individual undergoing testing for Lynch syndrome (PMID: 25980754). ClinVar contains an entry for this variant (Variation ID: 135983). 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.
Ambry Genetics RCV000130485 SCV000185354 uncertain significance Hereditary cancer-predisposing syndrome 2020-03-31 criteria provided, single submitter clinical testing The p.A419T variant (also known as c.1255G>A), located in coding exon 13 of the MUTYH gene, results from a G to A substitution at nucleotide position 1255. The alanine at codon 419 is replaced by threonine, an amino acid with similar properties. This variant has previously been reported in the literature with undefined clinical significance (Cheadle JP and Sampson JR. DNA Repair (Amst..) 2007 Mar;6:274-9; David SS et al. Nature. 2007 Jun;447:941-50; Kairupan C et al. Hered Cancer Clin Pract. 2007 Dec;5:199-209). In one study, it was observed in 1/1260 individuals who underwent clinical genetic testing for Lynch syndrome due to a history of a Lynch syndrome-associated cancer and/or polyps (Yurgelun MB et al. Gastroenterology. 2015 Sep;149:604-613.e20). This amino acid position is not well 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.
GeneDx RCV000590647 SCV000292630 uncertain significance not provided 2020-08-28 criteria provided, single submitter clinical testing Located in the critical NUDIX domain (Ruggieri 2013) Not observed at a significant frequency in large population cohorts (Lek 2016) In silico analysis supports that this missense variant does not alter protein structure/function Observed in individuals with Lynch-associated cancer and/or polyps or with glioblastoma (Lu 2015, Yurgelun 2015)
Illumina Clinical Services Laboratory,Illumina RCV000123142 SCV000357891 uncertain significance MYH-associated polyposis 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Counsyl RCV000123142 SCV000487370 uncertain significance MYH-associated polyposis 2016-07-19 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515285 SCV000611405 uncertain significance MYH-associated polyposis; Pilomatrixoma; Neoplasm of stomach 2017-05-23 criteria provided, single submitter clinical testing
Color Health, Inc RCV000130485 SCV000685557 uncertain significance Hereditary cancer-predisposing syndrome 2020-08-25 criteria provided, single submitter clinical testing This missense variant replaces alanine with threonine at codon 419 of the MUTYH protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with MUTYH-associated polyposis, colorectal cancer, glioblastoma, and suspected Lynch syndrome (PMID: 17581577, 25980754, 26689913, Insight-database.org), This variant has been identified in 19/282560 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001175350 SCV000697672 uncertain significance not specified 2019-11-11 criteria provided, single submitter clinical testing Variant summary: MUTYH c.1255G>A (p.Ala419Thr) results in a non-conservative amino acid change located in the C-terminal domain (IPR029119) and NUDIX hydrolase domains (IPR000086) 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 6.4e-05 in 251158 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in MUTYH causing MUTYH-associated Polyposis (6.4e-05 vs 0.0046), allowing no conclusion about variant significance. To our knowledge, there are no reports of c.1255G>A in individuals affected with MUTYH-associated Polyposis and no experimental evidence demonstrating an impact on protein function in the literature. c.1255G>A has been reported in an individual with Lynch syndrome (Yurgelun_2015) and in an individual with glioblastoma mulitforme (Lu_2015). These reports do not provide unequivocal conclusions about association of the variant with MUTYH-associated Polyposis. Eight other ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000590647 SCV000888300 uncertain significance not provided 2018-03-27 criteria provided, single submitter clinical testing

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