ClinVar Miner

Submissions for variant NM_001048171.1(MUTYH):c.1388C>T (p.Thr463Met) (rs767747402)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000168051 SCV000218704 uncertain significance MYH-associated polyposis 2020-08-14 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 477 of the MUTYH protein (p.Thr477Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs767747402, ExAC 0.006%). This sequence change was reported in an individual affected with multiple colorectal adenomas. However, two pathogenic alleles were also identified in the MUTYH gene. Because it was not determined on which chromosomes these three sequence changes reside, the clinical significance of this c.1430C>T substitution in MUTYH remained uncertain (PMID: 18515411). This sequence change is also known as c.1421C>T (T474M) in the literature. ClinVar contains an entry for this variant (Variation ID: 188159). 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: “probably damaging”; Align-GVGD: Class C1). 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. 5
Ambry Genetics RCV000562525 SCV000666457 uncertain significance Hereditary cancer-predisposing syndrome 2020-01-20 criteria provided, single submitter clinical testing The p.T477M variant (also known as c.1430C>T), located in coding exon 14 of the MUTYH gene, results from a C to T substitution at nucleotide position 1430. The threonine at codon 477 is replaced by methionine, an amino acid with similar properties. This alteration, designated as p.T474M, was identified in one individual from a multiple adenoma cohort; however, the individual also carried two pathogenic MUTYH mutations and phase of the alterations (cis or trans) was not determined (Dallosso AR et al. Gut. 2008 Sep;57:1252-5). 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.
Counsyl RCV000168051 SCV000800015 uncertain significance MYH-associated polyposis 2018-05-17 criteria provided, single submitter clinical testing
Color Health, Inc RCV000562525 SCV000903447 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-25 criteria provided, single submitter clinical testing

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