ClinVar Genomic variation as it relates to human health

The best available variant frequency is uninformative because it is below the disease allele frequency. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Occurs in multiple cases with a recessive pathogenic variant in the same gene. Assessment of experimental evidence suggests this variant results in abnormal protein function.

MUTYH p.Arg241Trp: This sequence change replaces arginine with tryptophan at codon 241 of the MUTYH protein (p.Arg241Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs34126013, ExAC 0.04%). This variant has been reported as heterozygous with another pathogenic variant in MUTYH in multiple individuals affected with polyposis and/or colorectal cancer (PMID: 24470512, 14991577, 27194394), and as homozygous in two siblings from a family affected with polyposis (PMID: 23561487). ClinVar contains an entry for this variant (Variation ID: 185274). In addition, in-silico prediction for this alteration shows pathogenic computational verdict based on 12 pathogenic predictions from BayesDel_addAF, DANN, DEOGEN2, EIGEN, FATHMM-MKL, LIST-S2, M-CAP, MVP, MutationAssessor, MutationTaster, REVEL and SIFT vs 1 benign prediction from PrimateAI. Experimental studies suggest that this missense change disrupts MUTYH protein function in vitro and in a bacteria-based functional assay (PMID: 15673720, 25820570). Therefore, this variant has been classified as Likely Pathogenic.

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 241 of the MUTYH protein (p.Arg241Trp). This variant is present in population databases (rs34126013, gnomAD 0.03%). This missense change has been observed in individuals with colorectal cancer and/or polyposis (PMID: 14991577, 23561487, 24470512, 27194394). This variant is also known as c.679C>T (p.Arg227Trp). ClinVar contains an entry for this variant (Variation ID: 185274). 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: 15673720, 25820570). This variant disrupts the p.Arg241 amino acid residue in MUTYH. Other variant(s) that disrupt this residue have been observed in individuals with MUTYH-related conditions (PMID: 19732775; Invitae), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.

This missense variant replaces arginine with tryptophan at codon 241 of the MUTYH protein. This variant is also known as c.637C>T (p.Arg213Trp) based on an alternative transcript (NM_001048174.2). Computational prediction tool 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 shown that this variant was deficient in A/8-oxoG binding and glycosylase activities , and failed to complement mutY-deficiency in Escherichia coli (PMID: 15673720, 25820570). This variant has been reported as biallelic with another pathogenic variant in multiple individuals affected with polyposis and/or colorectal cancer (PMID: 15366000, 19394335, 23561487, 24470512, 27194394, 28533537, 34704405). This variant has been identified in 18/281720 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.

The p.R241W pathogenic mutation (also known as c.721C>T), located in coding exon 9 of the MUTYH gene, results from a C to T substitution at nucleotide position 721. The arginine at codon 241 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been reported in conjunction with the common MUTYH founder mutations p.G396D (p.G382D) and p.Y179C (p.Y165C), other pathogenic/likely pathogenic MUTYH variants, and as homozygous in multiple patients with classic polyposis, attenuated polyposis, and/or colorectal cancer (Isidro G et al. Hum Mutat. 2004 Oct;24(4):353-4; Bai H et al. Nucleic Acids Res. 2005 Jan 26;33(2):597-604; Torrezan GT et al. Orphanet J Rare Dis. 2013 ;8:54; Guarinos C et al. Clin Cancer Res. 2014 Mar 1;20(5):1158-68; Win AK et al. Int J Cancer. 2016 Oct 1;139(7):1557-63; Khan N et al. Sci Rep. 2017 May 22;7(1):2214; Ambry internal data). Furthermore, the aforementioned co-occurrences are likely to be in trans due to multiple observances with different pathogenic or likely pathogenic MUTYH variants. In functional assays measuring glycosylase activity and DNA-binding activity, this variant demonstrated impaired protein function similar to the p.Y179C (p.Y165C) MUTYH founder mutation (Bai H et al. Nucleic Acids Res. 2005 Jan 26;33(2):597-604; Komine K et al. Hum Mutat. 2015 Jul;36(7):704-11). This alteration has also been identified in individuals diagnosed with male breast cancer, breast cancer and prostate cancer (Rizzolo P et al. Front Oncol, 2018 Dec;8:583; Lang GT et al. Ann Transl Med, 2020 Nov;8:1417; Nguyen-Dumont T et al. Int J Cancer, 2020 10;147:2142-2149). Of note, this alteration is also designated as p.R227W in published literature. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

The c.721C>T (p.Arg241Trp) variant, also referred to as c.679C>T (p.Arg227Trp), has been reported in five studies in which it is found in a total of six MYH-associated polyposis patients, including two siblings in a homozygous state and four patients in a compound heterozygous state with one of the common pathogenic MUTYH missense variants (Isidro et al. 2004; Fleischmann et al. 2004; Bai et al. 2005; Torrezan et al. 2013; Guarinos et al. 2014). The variant was absent from 354 controls (Fleischmann et al. 2004) but is reported at a frequency of 0.00042 in the South Asian population of the Exome Aggregation Consortium. Functional studies demonstrated that the p.Arg241Trp variant has a severe defect in adenine (A) /7,8-dihydro-8-oxo-guanine binding and therefore in the ability to catalyze adenine excision from A/GO mismatches, one of the main functions of the protein. The p.Arg241Trp variant was also shown to have no detectable glycosylase activity and failed to complement mut Y-deficiency in E. coli. The variant does not affect binding to the hMSH2/hMSH6 complex (Bai et al. 2005; Komine et al. 2015). Based on the collective evidence, the p.Arg241Trp variant is classified as likely pathogenic for MYH-associated polyposis.

Published functional studies demonstrate a damaging effect: deficient in glycosylase activity and partially deficient in base excision repair activity (Bai et al., 2005; Komine et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as c.679C>T p.(Arg227Trp); This variant is associated with the following publications: (PMID: 15366000, 15673720, 19506731, 28127763, 30604180, 32923906, 17931073, 25820570, 21171015, 14991577, 27194394, 27799157, 20663686, 23605219, 23507534, 24470512, 28533537, 28152038, 32338768, 33258288, 30787465, 30613976, 23108399, 11801590, 34704405, 23561487)

This missense variant replaces arginine with tryptophan at codon 241 of the MUTYH protein. This variant is also known as c.679C>T (p.Arg227Trp) based on an alternative transcript (NM_001048171). Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >=0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. Functional studies have shown that this variant disrupts MUTYH protein function (PMID: 15673720, 25820570). This variant has been reported as compound heterozygous with another pathogenic variant in multiple individuals affected with polyposis and/or colorectal cancer (PMID: 14991577, 15366000, 24470512, 27194394, 28533537, Color internal data), and as homozygous in two siblings affected with attenuated polyposis (parents were consanguineous) (PMID: 23561487). This variant has been identified in 18/281720 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.

MUTYH: PM3:Strong, PS3, PM2, PP3

The MUTYH p.Arg241Trp variant was identified in 2 of 822 proband chromosomes from individuals with colorectal adenomas (Isidro 2004, Fleischmann 2004). In both cases the variant occurred as a biallelic mutation in combination with the pathogenic MUTYH p.Gly382Asp mutation. The p.Arg241Trp variant was also identified in dbSNP (ID: rs34126013), HGMD, UMD (4X as a causal variant), and the “InSiGHT Colon Cancer Database”. The p.Arg241 residue is conserved across mammals and more distantly related organisms and 5/5 computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the p.Arg241Trp variant may impact the protein. In addition, one functional study found the variant to be severely defective in A/8-oxoG binding and glycosylase activities, and it failed to complement MutY-deficiency in E.coli (Bai 2005). In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.