Submissions for variant NM_001048174.2(MUTYH):c.649C>T (p.Arg217Cys)

gnomAD frequency: 0.00002  dbSNP: rs200495564

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129829	SCV000184645	pathogenic	Hereditary cancer-predisposing syndrome	2022-05-03	criteria provided, single submitter	clinical testing	The p.R245C pathogenic mutation (also known as c.733C>T), located in coding exon 9 of the MUTYH gene, results from a C to T substitution at nucleotide position 733. The arginine at codon 245 is replaced by cysteine, an amino acid with highly dissimilar properties. This mutation has been detected in the homozygous state in both Japanese and Portuguese APC mutation-negative adenomatous polyposis patients (Miyaki M et al. Mutat. Res. 2005 Oct 15;578(1-2):430-3; Olschwang S et al. Genet Test. 2007 Fall;11(3):315-20). This alteration was also seen in conjunction with a second MUTYH mutation in a 37 yo female with a history of colon cancer and approximately 50 colon polyps (Ruggieri V et al. Oncogene, 2013 Sep;32:4500-8). Current evidence supports codon 245 as a functionally important mutation hotspot, with multiple other missense alterations having been described as pathogenic or deficient in critical protein function in the literature (Aceto G et al. Hum Mutat. 2005 Oct;26(4):394; Vogt S et al. Gastroenterology. 2009 Dec;137(6):1976-85.e1-10; Bai H et al. Cancer Lett. 2007 May 18;250(1):74-81). In addition, a functional assay showed that p.R245C, which exists in a highly conserved and catalytic domain, results in partially defective protein expression levels compared to wild-type (Komine K et al. Hum. Mutat., 2015 Jul;36:704-11). Of note, this mutation is also described as p.R231C in published literature. This alteration has been detected in conjunction with a second pathogenic MUTYH mutation in an adenomatous polyposis patient without any detectable APC mutation (Ambry internal data). 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 available evidence, this alteration is classified as a pathogenic mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000034678	SCV000285964	pathogenic	Familial adenomatous polyposis 2	2023-11-21	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 245 of the MUTYH protein (p.Arg245Cys). This variant is present in population databases (rs200495564, gnomAD 0.02%). This missense change has been observed in individuals with familial adenomatous polyposis and/or MUTYH-associated polyposis (PMID: 15890374, 17949294, 23108399). This variant is also known as c.691C>T (p.Arg231Cys). ClinVar contains an entry for this variant (Variation ID: 41761). 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: 23108399, 25820570). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000482239	SCV000565259	pathogenic	not provided	2023-04-02	criteria provided, single submitter	clinical testing	Observed in the homozygous or compound heterozygous state in individuals with multiple polyps and colorectal cancer (Miyaki et al., 2005; Olschwang et al., 2007; Ruggieri et al., 2013; Gunaratnam et al., 2016; Furlan et al., 2017; Takao et al., 2018; Villy et al., 2021); Published functional studies demonstrate a damaging effect: absent DNA glycosylase activity, decreased MUTYH transcript and protein expression levels, and partially defective base excision repair (Ruggieri et al., 2013; Komine et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23605219, 22744763, 24620956, 19725997, 17949294, 15890374, 22703879, 21443744, 22865608, 25655665, 23108399, 25820570, 26684191, 28087410, 28152038, 30564557, 30787465, 34775073, 32980694, 31739127, 19506731, 17703316, 23507534, 29915346, 11801590, 31203172, 24569162, 31104418, 32821650, 32665031, 27021195, 29330641, 34026625, 34308104, 30487145, 28141798)
Color Diagnostics, LLC DBA Color Health	RCV000129829	SCV000685666	pathogenic	Hereditary cancer-predisposing syndrome	2023-04-05	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 245 of the MUTYH protein. This variant is also known as c.691C>T (p.Arg231Cys) based on an alternative transcript (NM_001048171). Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have reported this variant to be non-functional in MUTYH glycosylase assay (PMID: 23108399) and complementation of MUTYH-deficient bacteria (PMID: 25820570). This variant has been observed as a homozygous variant and compound heterozygous variant with a pathogenic co-variant in individuals affected with colorectal cancer and/or multiple colorectal adenomas and polyps (PMID: 15890374, 17949294, 23108399, 34775073). This variant has also been identified in an individual affected with breast cancer (PMID: 34026625). This variant has been identified in 14/250276 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000034678	SCV000697708	pathogenic	Familial adenomatous polyposis 2	2021-02-05	criteria provided, single submitter	clinical testing	Variant summary: MUTYH c.733C>T (p.Arg245Cys) results in a non-conservative amino acid change located in the HhH-GPD domain (IPR003265) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 250436 control chromosomes (gnomAD and publication data). This frequency is not higher than expected for a pathogenic variant in MUTYH causing MUTYH-Associated Polyposis (5.6e-05 vs 0.0046), allowing no conclusion about variant significance. c.733C>T has been reported in the literature in multiple individuals affected with adenomatous polyposis, either in homozygosity (Miyaki_2005, Olschwang_2007), or in compound heterozygosity with known- or likely pathogenic variants (Ruggieri_2013, Takao_2017, Furlan_2017). Functional studies indicated that the variant mildly diminishes RNA and protein expression, but completely abolishes DNA glycosylase activity (Ruggieri_2013), and partially impairs base excision repair (Komine_2015). Additionally, other variants at this amino acid position are reported in patients (p.Arg245His, p.Arg245Ser and p.Arg245Leu), suggesting this residue is critical for function. Seven ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (n=6) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Snyder Lab, Genetics Department, Stanford University	RCV000722047	SCV000853090	pathogenic	Familial colorectal cancer	2017-01-01	criteria provided, single submitter	research
CeGaT Center for Human Genetics Tuebingen	RCV000482239	SCV001248083	pathogenic	not provided	2017-01-01	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000034678	SCV002017623	pathogenic	Familial adenomatous polyposis 2	2019-01-08	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000482239	SCV002774365	pathogenic	not provided	2021-07-29	criteria provided, single submitter	clinical testing	This variant has been reported in multiple unrelated individuals with MUTYH-Associated Polyposis (MAP) and colorectal cancer in the published literature (PMIDs: 28141798 (2017), 23108399 (2013)),17949294 (2007), and 15890374 (2005)). Additionally, functional studies demonstrate a damaging effect of this variant on MUTYH protein function (PMIDs: 23108399 (2013) and 25820570 (2015)). Based on the available information, this variant is classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002496519	SCV002812489	pathogenic	Familial adenomatous polyposis 2; Gastric cancer	2022-04-19	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000034678	SCV004198899	pathogenic	Familial adenomatous polyposis 2	2024-03-24	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000034678	SCV004839206	pathogenic	Familial adenomatous polyposis 2	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 245 of the MUTYH protein. This variant is also known as c.691C>T (p.Arg231Cys) based on an alternative transcript (NM_001048171). Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have reported this variant to be non-functional in MUTYH glycosylase assay (PMID: 23108399) and complementation of MUTYH-deficient bacteria (PMID: 25820570). This variant has been observed as a homozygous variant and compound heterozygous variant with a pathogenic co-variant in individuals affected with colorectal cancer and/or multiple colorectal adenomas and polyps (PMID: 15890374, 17949294, 23108399, 34775073). This variant has also been identified in an individual affected with breast cancer (PMID: 34026625). This variant has been identified in 14/250276 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034678	SCV000043376	probably pathogenic	Familial adenomatous polyposis 2	2012-07-13	no assertion criteria provided	research	Converted during submission to Likely pathogenic.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000482239	SCV000592695	uncertain significance	not provided		no assertion criteria provided	clinical testing
Laboratory for Genotyping Development, RIKEN	RCV003162293	SCV002758367	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research