Submissions for variant NM_001048174.2(MUTYH):c.1217C>T (p.Thr406Met)

gnomAD frequency: 0.00001  dbSNP: rs587780084

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000235188	SCV000149666	uncertain significance	not provided	2023-06-04	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Also known as c.1259C>T, p.(Thr420Met); This variant is associated with the following publications: (PMID: 25980754, 28135145, 24728327, 23108399)
Ambry Genetics	RCV000115757	SCV000184172	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-21	criteria provided, single submitter	clinical testing	The p.T434M variant (also known as c.1301C>T), located in coding exon 13 of the MUTYH gene, results from a C to T substitution at nucleotide position 1301. The threonine at codon 434 is replaced by methionine, an amino acid with similar properties. This alteration was identified in a cohort of 1,260 individuals undergoing panel testing for Lynch syndrome due to having a diagnosis of a Lynch-associated cancer and/or polyps (Yurgelun MB et al. Gastroenterology 2015 Sep;149(3):604-613.e20). This alteration was also reported in 9/60,466 breast cancer cases as well as 5/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). Additionally, this alteration was identified in an individual diagnosed with colorectal cancer (DeRycke MS et al. Mol Genet Genomic Med, 2017 Sep;5:553-569). This amino acid position is not well 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	RCV000411291	SCV000487339	uncertain significance	Familial adenomatous polyposis 2	2016-03-03	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000411291	SCV000639269	uncertain significance	Familial adenomatous polyposis 2	2024-01-26	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 434 of the MUTYH protein (p.Thr434Met). This variant is present in population databases (rs587780084, gnomAD 0.008%). This missense change has been observed in individual(s) with clinical features of Lynch syndrome and/or colorectal cancer (PMID: 25980754, 28135145). This variant is also known as c.1259C>T (p.Thr420Met). ClinVar contains an entry for this variant (Variation ID: 127837). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The methionine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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.
Color Diagnostics, LLC DBA Color Health	RCV000115757	SCV000690516	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-07	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with methionine at codon 434 of the MUTYH protein. This variant is also known as c.1259C>T (p.Thr420Met) based on the NM_001048171.1 transcript. 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 an individual suspected of having Lynch syndrome (PMID: 25980754) and in an individual affected with colorectal cancer (PMID: 28135145). This variant has also been identified in 11/282736 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000235188	SCV000888306	uncertain significance	not provided	2022-12-27	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000046 (6/129092 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in an individual with colorectal cancer (PMID: 28135145 (2017)) and an individual with a Lynch syndrome associated cancer (PMID: 25980754 (2015)). In a large-scale breast cancer association study, the variant was observed in individuals with breast cancer as well as in unaffected individuals (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/MUTYH)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000235188	SCV002011065	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001818275	SCV002070313	uncertain significance	not specified	2020-07-30	criteria provided, single submitter	clinical testing	DNA sequence analysis of the MUTYH gene demonstrated a sequence change, c.1301C>T, in exon 13 that results in an amino acid change, p.Thr434Met. This sequence change has been described in the gnomAD database with a low overall population frequency of 0.004% (dbSNP rs587780084). Also known as c.1259C>T in the literature, this sequence change has been reported in an individual with colorectal cancer (PMID:28135145) and an individual with suspected Lynch syndrome (PMID: 25980754). The p.Thr434Met change affects a poorly conserved amino acid residue located in a domain of the MUTYH protein that is known to be functional. The p.Thr434Met substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Thr434Met change remains unknown at this time.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001818275	SCV002598690	uncertain significance	not specified	2024-07-01	criteria provided, single submitter	clinical testing	Variant summary: MUTYH c.1301C>T (p.Thr434Met) results in a non-conservative amino acid change located in the NUDIX hydrolase domain (IPR000086) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.3e-05 in 326508 control chromosomes (gnomAD and Okawa_2023). This frequency is not significantly higher than estimated for a pathogenic variant in MUTYH causing MUTYH-Associated Polyposis (4.3e-05 vs 0.0046), allowing no conclusion about variant significance. c.1301C>T (aka c.1259C>T (p.Thr420Met)) has been reported in the literature in the heterozygous state in an individual affected with suspected Lynch syndrome and/or polyps (Yurgelun_2015), and in a patient with colorectal cancer (Yurgelun_2017). The variant was also reported in a large study evaluating breast cancer cases and controls in the Breast Cancer Association Consortium (BCAC), in 9/60466 cases, and in 5/53461 controls (Dorling_2021 through LOVD). These reports do not provide unequivocal conclusions about association of the variant with MUTYH-Associated Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33471991, 36243179, 25980754, 28135145). ClinVar contains an entry for this variant (Variation ID: 127837). Based on the evidence outlined above, the variant was classified as uncertain significance.
All of Us Research Program, National Institutes of Health	RCV000411291	SCV004841115	uncertain significance	Familial adenomatous polyposis 2	2023-11-28	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with methionine at codon 434 of the MUTYH protein. This variant is also known as c.1259C>T (p.Thr420Met) based on the NM_001048171.1 transcript. 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 an individual suspected of having Lynch syndrome (PMID: 25980754) and in an individual affected with colorectal cancer (PMID: 28135145). This variant has also been identified in 11/282736 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.