Submissions for variant NM_001048174.2(MUTYH):c.1346C>T (p.Thr449Met)

dbSNP: rs767747402

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000168051	SCV000218704	uncertain significance	Familial adenomatous polyposis 2	2023-11-27	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 477 of the MUTYH protein (p.Thr477Met). This variant is present in population databases (rs767747402, gnomAD 0.003%). This missense change has been observed in individual(s) with colorectal adenomas (PMID: 18515411). This variant is also known as c.1421C>T (T474M). ClinVar contains an entry for this variant (Variation ID: 188159). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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	RCV000562525	SCV000666457	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-04	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, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Counsyl	RCV000168051	SCV000800015	uncertain significance	Familial adenomatous polyposis 2	2018-05-17	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000562525	SCV000903447	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-01	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with methionine at codon 477 of the MUTYH protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MUTYH-related disorders in the literature. This variant has been identified in 4/251488 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.
GeneDx	RCV001589047	SCV001816961	uncertain significance	not provided	2022-10-12	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Co-occurred with two pathogenic MUTYH variants in an individual with colorectal cancer, multiple colorectal adenomas, and gastric antral adenomas (Dallosso et al., 2008); Also known as MUTYH Thr474Met; This variant is associated with the following publications: (PMID: 23108399, 18515411)
Baylor Genetics	RCV000168051	SCV004198929	uncertain significance	Familial adenomatous polyposis 2	2023-11-23	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000168051	SCV004827795	uncertain significance	Familial adenomatous polyposis 2	2023-09-04	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with methionine at codon 477 of the MUTYH protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MUTYH-related disorders in the literature. This variant has been identified in 4/251488 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.