Submissions for variant NM_001048174.2(MUTYH):c.469C>T (p.Arg157Trp)

gnomAD frequency: 0.00001  dbSNP: rs750592289

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000478161	SCV000567147	likely pathogenic	not provided	2019-11-12	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Also known as c.511C>T, p.Arg171Trp; This variant is associated with the following publications: (PMID: 19953527, 25820570, 18091433, 20418187, 25638157, 32658311)
Ambry Genetics	RCV000562580	SCV000670141	uncertain significance	Hereditary cancer-predisposing syndrome	2024-11-07	criteria provided, single submitter	clinical testing	The p.R185W variant (also known as c.553C>T), located in coding exon 7 of the MUTYH gene, results from a C to T substitution at nucleotide position 553. The arginine at codon 185 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration was first reported in a male patient with colon cancer at age 49 and 90-100 polyps (Cattaneo F et al Genet. Med. 2007 Dec; 9(12):836-41). One functional analysis of this alteration using human proteins from a bacterial system suggests this alteration results in severe reduction in binding affinity as well as reduced adenine removal activity compared to the wild-type protein (D'Agostino VG et al DNA Repair (Amst.). 2010 Jun; 9(6):700-7). An additional study in which this alteration was expressed in Mutyh-/- mouse defective cells showed dysfunctional Base Excision Repair and goes on to suggest that the mutant protein produced by this alteration revealed a more pronounced phenotype than the simple loss of the Mutyh protein, suggesting a sort of dominant-negative effect (Molatore S et al Hum. Mutat. 2010 Feb; 31(2):159-66). Of note, this alteration is also designated as p.R171W (c.511C>T) in some published literature. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
CeGaT Center for Human Genetics Tuebingen	RCV000478161	SCV000891830	likely pathogenic	not provided	2018-08-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000562580	SCV000913518	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-22	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 185 of the MUTYH protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown that this variant has no detectable glycosylase activity and reduced substrate binding (PMID: 19953527, 20418187). This variant has been reported in individuals affected with colorectal cancer and polyposis (PMID: 18091433) or breast cancer (PMID: 32658311). This variant has been identified in 2/251446 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000803247	SCV000943109	uncertain significance	Familial adenomatous polyposis 2	2024-05-21	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 185 of the MUTYH protein (p.Arg185Trp). This variant is present in population databases (rs750592289, gnomAD 0.004%). This missense change has been observed in individual(s) with polyposis, colorectal cancer, and/or breast cancer (PMID: 18091433, 32658311). ClinVar contains an entry for this variant (Variation ID: 419386). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Not Available". The tryptophan amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change affects MUTYH function (PMID: 19953527, 20418187, 22252118). 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.
Baylor Genetics	RCV000803247	SCV004198825	uncertain significance	Familial adenomatous polyposis 2	2024-03-26	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000803247	SCV004837345	uncertain significance	Familial adenomatous polyposis 2	2023-06-26	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 185 of the MUTYH protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown that this variant has no detectable glycosylase activity and reduced substrate binding (PMID: 19953527, 20418187). This variant has been reported in individuals affected with colorectal cancer and polyposis (PMID: 18091433) or breast cancer (PMID: 32658311). This variant has been identified in 2/251446 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.
Center of Medical Genetics and Primary Health Care	RCV001004834	SCV000987256	uncertain significance	Familial cancer of breast	2020-07-15	no assertion criteria provided	research	ACMG Guidelines 2015 criteria The MUTYH gene variant p.Arg185Trp is in exon 7 and in the HhH-GPD domain (V118-249W aa) with a function in base-excision repair (PMID: 10706276). Experimental studies showed this missense change abolishes the glycosylase activity of the MUTYH protein (PMID: 20418187, 19953527) (PS3 Pathogenic Strong). It is in a mutation hotspot of 7 pathogenic, including missense pathogenic variants (PM1 Pathogenic Moderate). The allele frequency in GnomAD exomes is 0.00000795 which is less the threshold 0.0001 for recessive gene MUTYH, and the variant is not found in GnomAD genomes (PM2 Pathogenic Moderate). Meantime, majority of missense variants detected in MUTYH are pathogenic and known cause of disease (PP2 Pathogenic Supporting). In our study this variant was found in a 54-year-old female patient with unilateral breast cancer and a family history of cancer. Based on the evidence above we classified this variant as a Variant of Unknown Significance.
Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences	RCV001643192	SCV001852740	pathogenic	Breast carcinoma	2021-09-10	no assertion criteria provided	clinical testing