ClinVar Miner

Submissions for variant NM_001128425.1(MUTYH):c.44T>C (p.Met15Thr) (rs201163858)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000467236 SCV000545767 uncertain significance MYH-associated polyposis 2020-10-05 criteria provided, single submitter clinical testing This sequence change replaces methionine with threonine at codon 15 of the MUTYH protein (p.Met15Thr). The methionine residue is highly conserved and there is a moderate physicochemical difference between methionine and threonine. This variant is present in population databases (rs201163858, ExAC 0.009%). This variant has not been reported in the literature in individuals with MUTYH-related disease. ClinVar contains an entry for this variant (Variation ID: 406849). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Benign; Align-GVGD: Class C). A different missense substitution at this codon (p.Met15Val) has been reported to be deleterious (PMID: 24691292). Functional studies have shown that the p.Met15Val variant inactivates the start codon of two alternative transcripts encoding nuclear MUTYH isoforms (β and γ) that are highly expressed in the ascending colon (PMID: 24691292). These results indicate that the methionine residue is important for MUTYH protein function. 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. 6
GeneDx RCV000478752 SCV000566692 uncertain significance not provided 2018-02-20 criteria provided, single submitter clinical testing This variant is denoted MUTYH c.44T>C at the cDNA level, p.Met15Thr (M15T) at the protein level, and results in the change of a Methionine to a Threonine (ATG>ACG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MUTYH Met15Thr was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located within the RPA binding domain (Ruggieri 2013). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MUTYH Met15Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. Of note, MUTYH-Associated Polyposis (MAP) is a recessive condition associated with two MUTYH pathogenic variants on opposite chromosomes.
Ambry Genetics RCV000571566 SCV000666473 likely pathogenic Hereditary cancer-predisposing syndrome 2020-07-14 criteria provided, single submitter clinical testing The p.M15T variant (also known as c.44T>C), located in coding exon 2 of the MUTYH gene, results from a T to C substitution at nucleotide position 44. The methionine at codon 15 is replaced by threonine, an amino acid with similar properties. This alteration was identified in trans with a pathogenic founder mutation in MUTYH through familial studies in a proband with early-onset colorectal cancer as well as a history of greater than 20 polyps (Ambry internal data). This alteration was also identified in a proband with greater than 100 adenomatous polyps and was seen in conjunction with a different pathogenic MUTYH founder mutation, which has a high probability of being in trans given that this alteration has co-occurred with different founder mutations (Ambry internal data). A different alteration affecting this amino acid, p.M15V, has been reported as co-occurring with a pathogenic MUTYH mutation in three siblings with colorectal cancer in their 40s and a history of multiple adenomas in their 50s-60s (Seguí N et al. Gut. 2015 Feb;64:355-6). Based on data from the Genome Aggregation Database (gnomAD), the C allele has an overall frequency of approximately 0.000795% (2/251474) total alleles studied. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Color Health, Inc RCV000571566 SCV001344067 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-19 criteria provided, single submitter clinical testing

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