Submissions for variant NM_001048174.2(MUTYH):c.307T>A (p.Trp103Arg)

dbSNP: rs730881832

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212700	SCV000211401	pathogenic	not provided	2024-04-04	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect based on results of a complementation assay in E. coli (PMID: 25820570); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 19822006, 26681312, 19732775, 12853198, 19032956, 19394335, 19725997, 17581577, 30604180, 25820570)
Ambry Genetics	RCV000160751	SCV000216757	pathogenic	Hereditary cancer-predisposing syndrome	2024-06-11	criteria provided, single submitter	clinical testing	The p.W131R pathogenic mutation (also known as c.391T>A) is located in coding exon 5 of the MUTYH gene. This alteration results from a T to A substitution at nucleotide position 391. The tryptophan at codon 131 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been detected in conjunction with the MUTYH p.Y179C pathogenic mutation in an individual with 152 colorectal polyps diagnosed at age 30 (Sampson JR et al. Lancet 2003 Jul; 362(9377):39-41; Vogt S et al. Gastroenterology 2009 Dec; 137(6):1976-85.e1-10). It was also detected in a patient diagnosed with colon cancer and colon polyps who underwent multi-gene panel testing (Susswein LR et al. Genet Med. 2016 Aug;18(8):823-32). Functional and structural assays demonstrated that this alteration is functionally defective and predicted to disrupt DNA-binding ability (David SS et al. Nature 2007 Jun;447(7147):941-50; Komine K et al. Hum Mutat. 2015 Jul;36(7):704-11). This alteration is also known as p.W117R in the published literature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000701601	SCV000830411	pathogenic	Familial adenomatous polyposis 2	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 131 of the MUTYH protein (p.Trp131Arg). This variant is present in population databases (rs730881832, gnomAD 0.0009%). This missense change has been observed in individual(s) with colon cancer and MUTYH-associated polyposis (PMID: 12853198, 19032956, 19394335, 19732775, 25820570, 26681312; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as Trp117Arg. ClinVar contains an entry for this variant (Variation ID: 182688). 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. Experimental studies have shown that this missense change affects MUTYH function (PMID: 25820570). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000701601	SCV000917811	pathogenic	Familial adenomatous polyposis 2	2021-06-26	criteria provided, single submitter	clinical testing	Variant summary: MUTYH c.391T>A (p.Trp131Arg) results in a non-conservative amino acid change located in the HhH-GPD domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. 3/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 251412 control chromosomes (gnomAD). c.391T>A has been reported in the literature in individuals affected with MUTYH-Associated Polyposis (e.g. Sampson_2003, Jones_2009, Susswein_2016, Sutcliffe_2019). These data indicate that the variant is likely to be associated with disease. A functional study, Komine_2015, found the variant to be defective in base excision repair in a MUTY-deficient E. coli complementation assay. Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000160751	SCV001343955	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-08-09	criteria provided, single submitter	clinical testing	This missense variant replaces tryptophan with arginine at codon 131 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). A functional study has shown that the variant protein is severely defective in a complementation assay conducted in E. coli (PMID: 25820570). This variant has been reported in two individuals with biallelic mutations in MUTYH and affected with MUTYH-associated polyposis, with one individual carrying the pathogenic co-variant c.536A>G (PMID: 12853198, 19032956, 19394335, 19732775, 30604180). This variant has also been reported in an individual affected with colon cancer and polyps (PMID 26681312). This variant has been identified in 1/251412 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
AiLife Diagnostics, AiLife Diagnostics	RCV000212700	SCV002501902	likely pathogenic	not provided	2021-08-18	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000160751	SCV002532285	pathogenic	Hereditary cancer-predisposing syndrome	2020-12-08	criteria provided, single submitter	curation
Baylor Genetics	RCV000701601	SCV004199441	pathogenic	Familial adenomatous polyposis 2	2021-07-14	criteria provided, single submitter	clinical testing