Submissions for variant NM_001048174.2(MUTYH):c.737G>A (p.Arg246Gln)

gnomAD frequency: 0.00023  dbSNP: rs149866955

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000123156	SCV000166460	pathogenic	Familial adenomatous polyposis 2	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 274 of the MUTYH protein (p.Arg274Gln). This variant is present in population databases (rs149866955, gnomAD 0.04%). This missense change has been observed in individual(s) with clinical features of MUTYH-associated polyposis (PMID: 11818965, 19245865, 24444654, 27829682, 29458332; 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 R260Q or R246Q. ClinVar contains an entry for this variant (Variation ID: 41764). 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 glutamine 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: 18534194, 19443904). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000129219	SCV000183970	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-07-15	criteria provided, single submitter	clinical testing	The p.R274Q variant (also known as c.821G>A), located in coding exon 10 of the MUTYH gene, results from a G to A substitution at nucleotide position 821. The arginine at codon 274 is replaced by glutamine, an amino acid with highly similar properties. This variant has been identified in conjunction with different pathogenic MUTYH founder mutations in individuals with adenomatous polyposis; however, the phase (whether in cis or trans) is not confirmed (Ambry internal data). In a large study that analyzed monoallelic carriers, there was no significant difference in the monoallelic p.R274Q frequency between colorectal patients and controls (Cleary SP et al. Gastroenterology. 2009 Apr;136:1251-60). This variant has also been reported in an individual diagnosed with colorectal cancer and an individual diagnosed with uterine cancer (Dominguez-Valentin M et al. BMC Med. Genet. 2018 Feb;19:26; Levine MD et al. JCO Precis Oncol, 2021 11;5:1588-1602). In vitro analyses have demonstrated significantly reduced DNA glycosylase and DNA binding activities compared to wild type MUTYH (Ali M et al. Gastroenterology. 2008 Aug;135:499-507; Forsbring M et al. Carcinogenesis. 2009 Jul;30:1147-54). Based on internal structural analysis, this variant is anticipated to result in a decrease in structural stability and protein activity (Luncsford PJ et al. J Mol Biol, 2010 Oct;403:351-70). Of note, this alteration is also designated as p.R260Q (c.779G>A) in published literature. 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 majority of available evidence to date, this variant is likely to be pathogenic.
GeneDx	RCV000034681	SCV000211407	likely pathogenic	not provided	2023-08-28	criteria provided, single submitter	clinical testing	Observed in the heterozygous state in individuals with colorectal cancer and/or polyps and other cancers (Cleary et al., 2009; Win et al., 2014; Tung et al., 2015; Mandelker et al., 2017; Ricci et al., 2017; Dominguez-Valentin et al., 2018; Levine et al., 2021; Duzkale et al., 2021); Published functional studies are inconclusive: reduced glycosylation compared to wild type (Ali et al., 2008; Forsbring et al., 2009); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(Arg260Gln) or p.(Arg271Gln); This variant is associated with the following publications: (PMID: 28301460, 29458332, 18534194, 25318351, 22703879, 25820570, 16134147, 16557584, 19732775, 27194394, 26202870, 27799157, 27276934, 26976419, 11818965, 21171015, 19245865, 19443904, 27829682, 28873162, 27498913, 27443514, 29490034, 25186627, 24444654, 35668106, 36260238, 36556183, 34271781, 34994648, 32885271, 32283892, 33471991, 11092888, 11160897, 36243179)
Counsyl	RCV000123156	SCV000487372	uncertain significance	Familial adenomatous polyposis 2	2016-08-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000613933	SCV000697712	uncertain significance	not specified	2023-10-05	criteria provided, single submitter	clinical testing	Variant summary: MUTYH c.821G>A (p.Arg274Gln) results in a conservative amino acid change located in the HhH-GPD domain (IPR003265) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00018 in 256736 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in MUTYH causing MUTYH-Associated Polyposis (0.00018 vs 0.0046), allowing no conclusion about variant significance. c.821G>A has been reported in the literature in an individual affected with colorectal cancer with tumor positive for two other pathogenic APC variants (Al-Tassan_2002), an MSI-high, MSH2 negative colorectal cancer patient with co-occurring MSH2 pathogenic variants (Win_2015), a patient with Breast/Uterus cancers along with a VUS variant in ATM gene (Bhai_2021), as a sole variant in the setting of colorectal cancer (Cleary_2009, Yurgelun_2017), a patient with breast cancer with a co-occurring pathogenic ATM variant (Bunnell_2017), as a sole variant in the setting of primary sclerosing cholangitis (Forsbring_2009), endometrial carcinoma cohort (Ring_2016), breast cancer testing cohort (Yorczyk_2015), and suspected MUTYH polyposis cohort (Ricci_2016). These report(s) do not provide unequivocal conclusions about association of the variant with MUTYH-Associated Polyposis. Co-occurrences with other pathogenic variant(s) have been reported (ATM c.170G>A, p.Trp57X; MSH2 c.136_164del, p.His46GlyfsTer26; CHEK2 c.1100delC, p.Thr367Metfs*15), providing supporting evidence for a benign role (Bunnell_2017, Win_2015, Bhai_2021). At least two publications report conflicting experimental evidence evaluating an impact on protein function with partially reduced or defective glycosylase and DNA binding activity in vitro (example, Ali_2008, Forsbring_2009). Therefore, these reports do not allow convincing conclusions about the variant effect in vivo.The following publications have been ascertained in the context of this evaluation (PMID: 11818965, 18534194, 34326862, 27276934, 19245865, 19443904, 22703879, 28873162, 27829682, 27443514, 26202870, 25318351, 28135145). Ten submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments (PATH, n=1, Likely PATH, n=2, VUS, n=7). Based on the evidence outlined above, the variant was classified as uncertain significance.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000613933	SCV000711715	uncertain significance	not specified	2019-01-31	criteria provided, single submitter	clinical testing	The p.Arg274Gln variant in MUTYH has been reported in the heterozygous state in at least 11 patients with colorectal cancer (one with a pathogenic variant in MSH2), colorectal polyps, or primary sclerosing cholangitis (Al-Tassan 2002, Forsbring 2009, Johnston 2012, Win 2014, Win 2015). One study investigating the risk of developing colorectal cancer (CRC) in individuals with monoallelic and biallelic MUTYH variants reported the p.Arg274Gln variant with another pathogenic variant (Gly396Asp) in the biallelic state in one individual (Win 2014). Although no clinical details were provided, the authors reported near complete penetrance for biallelic MUTYH variant carriers, making it likely that the individual had CRC. In vitro functional studies provide some evidence that this variant results in impaired glycosylase and DNA binding activity (Ali 2008, Forsbring 2009). However, these types of assays may not accurately represent biological function. This variant has been also been identified in 0.04% (45/128216) of European chromosomes by the Genome Aggregation Database (GnomAD, http://gnomad.broadinstitute.org) and is reported in ClinVar (Variation ID:41764). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Arginine (Arg) at position 274 is not conserved in mammals or evolutionarily distant species and the change to glutamine (Gln) is present in 2 mammals (lesser Egyptian jerboa and cape elephant shrew), raising the possibility that this change may be tolerated. Additional computational tools suggest that the p.Arg274Gln variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Arg274Gln variant is uncertain. ACMG/AMP Criteria applied: PS3_supporting.
PreventionGenetics, part of Exact Sciences	RCV000034681	SCV000806368	uncertain significance	not provided	2017-05-04	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129219	SCV000902654	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-12	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 274 of the MUTYH protein. This variant is also known as Arg260Gln based on the NM_001048171.1 transcript. 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 of this variant have described partial functional deficits in MUTYH glycosylase and DNA binding activities (PMID: 18534194, 19443904). This variant has been reported in the compound heterozygous state in individuals affected with colorectal cancer or polyposis (PMID: 24444654; ClinVar SCV000166460; external laboratory communication). This variant has also been observed in biallelic individuals unaffected with colorectal cancer or polyposis (PMID: 35668106; ClinVar SCV000166460; external laboratory communication; Color internal data). This variant has been seen in heterozygous individuals affected with colorectal cancer or polyposis (PMID: 11818965, 19245865, 24444654, 24470512, 26202870, 27829682, 28873162, 29458332, 34271781), and some of these individuals also carried pathogenic variants in other genes that could explain the observed phenotype (PMID: 26202870, 27276934; Color internal data). This variant has been identified in 53/281410 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant at this position (p.Arg274Trp) is consistently classified as Likely Pathogenic suggesting that the position is important for function (ClinVar Variation ID: 449417). 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	RCV000034681	SCV001134486	likely pathogenic	not provided	2023-06-16	criteria provided, single submitter	clinical testing	The MUTYH c.821G>A (p.Arg274Gln) variant has been reported in the published literature in affected individuals with colorectal cancer (PMIDs: 19245865 (2009), 24444654 (2014), 26202870 (2015), 28135145 (2017), 29458332 (2018), 32283892 (2020), 34271781 (2021)), including a monoallelic carrier suspected of having MUTYH-associated polyposis (PMID: 27829682 (2016)). This variant has also been identified in individuals affected with primary sclerosing cholangitis (PMID: 19443904 (2009)), breast cancer (PMIDs: 26976419 (2016), 32885271 (2021)), endometrial cancer (PMID: 27443514 (2016)), and prostate cancer (PMID: 28873162 (2017)). In a large scale breast cancer association study, the variant was observed in control individuals as well as in breast cancer cases (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/MUTYH)). Functional studies have shown that the variant causes significantly reduced glycosylase activity that was 15-21% of the wild-type, while observations about DNA-binding activity are conflicting (PMIDs: 18534194 (2008), 19443904 (2009)). The frequency of this variant in the general population, 0.00035 (45/128216 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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 damaging. Based on the available information, this variant is classified as likely pathogenic.
Illumina Laboratory Services, Illumina	RCV000123156	SCV001255472	uncertain significance	Familial adenomatous polyposis 2	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Sema4, Sema4	RCV000129219	SCV002532333	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-23	criteria provided, single submitter	curation
Baylor Genetics	RCV000123156	SCV004198803	likely pathogenic	Familial adenomatous polyposis 2	2023-10-23	criteria provided, single submitter	clinical testing
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034681	SCV000043375	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000034681	SCV001550270	uncertain significance	not provided		no assertion criteria provided	clinical testing	The MUTYH p.Arg274Gln variant was identified in 17 of 26630 proband chromosomes (frequency: 0.0006) from individuals or families with colorectal cancer and was present in 1 of 5604 control chromosomes (frequency: 0.0002) from healthy individuals (Cleary 2009, Win 2014). The variant was also identified in dbSNP (ID: rs149866955) as "With other allele", and in ClinVar (classified as likely benign by Color; as uncertain significance by Invitae, Ambry Genetics and six other submitters). The variant was not identified in UMD-LSDB. The variant was identified in control databases in 50 of 275880 chromosomes at a frequency of 0.0002 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 3 of 23776 chromosomes (freq: 0.0001), Latino in 2 of 34402 chromosomes (freq: 0.00006), European in 45 of 125728 chromosomes (freq: 0.0004), while the variant was not observed in the Other, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. Several invitro functional studies suggest the variant has reduced glycosylase activity and DNA binding activity (Ali 2008, Forsbring 2009). The p.Arg274 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
GenomeConnect - Invitae Patient Insights Network	RCV000123156	SCV001749587	not provided	Familial adenomatous polyposis 2		no assertion provided	phenotyping only	Variant reported in multiple GenomeConnect-Invitae Patient Insights Network participants. Variant interpreted as Likely pathogenic by Invitae most recently on 06-11-2020 and 06-10-2020. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.