1-45332278-C-T
Variant summary
Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1PM5PP5
The NM_001128425.2(MUTYH):c.821G>A(p.Arg274Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000323 in 1,613,960 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R274W) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001128425.2 missense
Scores
Clinical Significance
Conservation
Publications
- familial adenomatous polyposis 2Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen, G2P
- colorectal cancerInheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
- familial ovarian cancerInheritance: AD, AR Classification: NO_KNOWN Submitted by: ClinGen
- hereditary breast carcinomaInheritance: AD, AR Classification: NO_KNOWN Submitted by: ClinGen
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ACMG classification
Our verdict: Uncertain_significance. The variant received 5 ACMG points.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| MUTYH | ENST00000710952.2 | c.821G>A | p.Arg274Gln | missense_variant | Exon 10 of 16 | NM_001128425.2 | ENSP00000518552.2 | |||
| MUTYH | ENST00000456914.7 | c.737G>A | p.Arg246Gln | missense_variant | Exon 10 of 16 | 1 | NM_001048174.2 | ENSP00000407590.2 | ||
| ENSG00000288208 | ENST00000671898.1 | n.1325G>A | non_coding_transcript_exon_variant | Exon 14 of 21 | ENSP00000499896.1 |
Frequencies
GnomAD3 genomes 0.000210 AC: 32AN: 152162Hom.: 0 Cov.: 33 show subpopulations
GnomAD2 exomes AF: 0.000172 AC: 43AN: 250036 AF XY: 0.000221 show subpopulations
GnomAD4 exome AF: 0.000335 AC: 489AN: 1461798Hom.: 0 Cov.: 36 AF XY: 0.000334 AC XY: 243AN XY: 727198 show subpopulations
Age Distribution
GnomAD4 genome 0.000210 AC: 32AN: 152162Hom.: 0 Cov.: 33 AF XY: 0.000188 AC XY: 14AN XY: 74324 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
not provided Pathogenic:3Uncertain:4
The MUTYH c.821G>A; p.Arg274Gln variant (rs149866955, ClinVar Variation ID: 41764), also known as Arg260Gln in traditional nomenclature, is reported in the literature in individuals affected with colorectal cancer (CRC) or suspected MUTYH-associated polyposis, including a subset of individuals compound heterozygous for a second MUTYH pathogenic variant (Al-Tassan 2002, Cleary 2009, Dominguez-Valentin 2018, Duzkale 2021, Erdem 2020, Georgeson 2022, Ricci 2017, Win 2014, Yurgelun 2017). However, some individuals also carried variants in other genes that may explain the phenotype (Duzkale 2021, Win 2014). Additionally, this variant has been reported in individuals with non-CRC cancer (selected references: Bhai 2021, Levine 2021, Lerner-Ellis 2021) and primary sclerosing cholangitis (Forsbring 2009). This variant is found in the general population with an overall allele frequency of 0.02% (53/281,410 alleles) in the Genome Aggregation Database (v2.1.1). In addition, another variant at this codon (c.820C>T; p.Arg274Trp) has been reported in individuals with CRC (Aceto 2005, Aretz 2006). Computational analyses predict that the p.Arg274Gln variant is deleterious (REVEL: 0.826). In vitro functional analyses demonstrate reduced glycosylase activity, but conflicting results of DNA binding activity compared to wild type (Ali 2008, Forsbring 2009). Based on available information, this variant is considered to be likely pathogenic. References: Aceto G et al. Mutations of APC and MYH in unrelated Italian patients with adenomatous polyposis coli. Hum Mutat. 2005 Oct;26(4):394. PMID: 16134147. Ali M et al. Characterization of mutant MUTYH proteins associated with familial colorectal cancer. Gastroenterology. 2008 Aug;135(2):499-507. PMID: 18534194. Al-Tassan N et al. Inherited variants of MYH associated with somatic G:C-->T:A mutations in colorectal tumors. Nat Genet. 2002 Feb;30(2):227-32. PMID: 11818965. Aretz S et al. MUTYH-associated polyposis: 70 of 71 patients with biallelic mutations present with an attenuated or atypical phenotype. Int J Cancer. 2006 Aug 15;119(4):807-14. PMID: 16557584. Bhai P et al. Analysis of Sequence and Copy Number Variants in Canadian Patient Cohort With Familial Cancer Syndromes Using a Unique Next Generation Sequencing Based Approach. Front Genet. 2021 Jul 13;12:698595. PMID: 34326862. Cleary SP et al. Germline MutY human homologue mutations and colorectal cancer: a multisite case-control study. Gastroenterology. 2009 Apr;136(4):1251-60. PMID: 19245865. Dominguez-Valentin M et al. Identification of genetic variants for clinical management of familial colorectal tumors. BMC Med Genet. 2018 Feb 20;19(1):26. PMID: 29458332. Duzkale N et al. Investigation of Hereditary Cancer Predisposition Genes of Patients with Colorectal Cancer: Single-centre Experience. J Coll Physicians Surg Pak. 2021 Jul;31(7):811-816. PMID: 34271781. Erdem HB and Bahsi T. Spectrum of germline cancer susceptibility gene mutations in Turkish colorectal cancer patients: a single center study. Turk J Med Sci. 2020 Jun 23;50(4):1015-1021. PMID: 32283892. Forsbring M et al. Catalytically impaired hMYH and NEIL1 mutant proteins identified in patients with primary sclerosing cholangitis and cholangiocarcinoma. Carcinogenesis. 2009 Jul;30(7):1147-54. PMID: 19443904. Georgeson P et al. Identifying colorectal cancer caused by biallelic MUTYH pathogenic variants using tumor mutational signatures. Nat Commun. 2022 Jun 6;13(1):3254. PMID: 35668106. Lerner-Ellis J et al. Multigene panel testing for hereditary breast and ovarian cancer in the province of Ontario. J Cancer Res Clin Oncol. 2021 Mar;147(3):871-879. PMID: 32885271. Levine MD et al. Up-Front Multigene Panel Testing for Cancer Susceptibility in Patients With Newly Diagnosed Endometrial Cancer: A Multicenter Prospective Study. JCO Precis Oncol. 2021 Nov;5:1588-1602. PMID: 34994648. Ricci MT et al. Type and frequency of MUTYH variants in Italian patients with suspected MAP: a retrospective multic -
The p.Arg274Gln variant in MUTYH has been reported in the heterozygous state in at least 14 patients with colorectal cancer (one with a pathogenic variant in MSH2), colorectal polyps, or primary sclerosing cholangitis (Al-Tassan 2002 PMID: 11818965, Forsbring 2009 PMID: 19443904, Johnston 2012 PMID: 22703879, Win 2014 PMID: 24444654, Win 2015 PMID: 26202870, Erdem 2020 PMID: 32283892, Duzkale 2020 PMID: 34271781, Ricci 2016 PMID: 27829682). 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 PMID: 24444654). 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 PMID: 18534194, Forsbring 2009 PMID: 19443904). However, these types of assays may not accurately represent biological function. This variant has been also been identified in 0.04% (28/68018) 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. Another variant involving this codon (p.Arg274Trp) has been identified in individuals with MUTYH-associated polyposis (MAP) and is classified as likely pathogenic by this laboratory. In summary, the clinical significance of the p.Arg274Gln variant is uncertain. ACMG/AMP Criteria applied: PM5, PS3_supporting, PP3, PM3_P. -
Published functional studies are inconclusive: reduced glycosylation compared to wild type (PMID: 18534194, 19443904); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(Arg260Gln) or p.(Arg271Gln); Observed in the heterozygous state in individuals with colorectal cancer and/or polyps and other cancers (PMID: 19245865, 24444654, 25186627, 28873162, 27829682, 29458332, 34271781, 34994648, 34326862); 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, 36243179, 11092888, 11160897, 38062336, 34326862, 37937776) -
MUTYH: PM5, PS3:Moderate -
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. -
The MUTYH c.821G>A (p.Arg274Gln) variant (also known as Arg260Gln) has been reported in the published literature in individuals with colorectal cancer (PMIDs: 19245865 (2009), 24444654 (2014), 26202870 (2015), 28135145 (2017), 29458332 (2018), 32283892 (2020), 34271781 (2021), 35668106 (2022)), including an individual with suspected MUTYH-associated polyposis without a second MUTYH variant identified (PMID: 27829682 (2016)). This variant has also been reported in individuals with primary sclerosing cholangitis (PMID: 19443904 (2009)), breast cancer (PMIDs: 26976419 (2016), 32885271 (2021), 34326862 (2021)), endometrial cancer (PMID: 27443514 (2016)), and prostate cancer (PMIDs: 28873162 (2017)). In large scale case-control studies, this variant was observed in individuals with breast cancer as well as in reportedly healthy individuals (PMIDs: 36243179 (2022), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared)). Functional studies indicate this variant causes significantly reduced glycosylase activity that was 15-21% of the wild-type, with neutral/moderate effect on DNA binding (PMIDs: 18534194 (2008), 19443904 (2009)). The frequency of this variant in the general population, 0.00076 (20/26062 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, this variant is classified as likely pathogenic. -
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Familial adenomatous polyposis 2 Pathogenic:3Uncertain:3Other:1
The MUTYH c.821G>A (p.Arg274Gln) missense change has a maximum subpopulation frequency of 0.035% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL predicts a deleterious effect on protein function, and in vitro analyses have demonstrated reduced functional activities compared to wild type MUTYH (PMID: 18534194, 19443904). This variant has been reported in conjunction with another pathogenic variant in an individual with colorectal cancer (PMID: 24444654). In summary, this variant meets criteria to be classified as likely pathogenic.? -
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. 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, 35668106; ClinVar SCV000166460, SCV000183970.11, SCV000487372.2; external laboratory communication). This variant has also been observed in biallelic individuals unaffected with colorectal cancer or polyposis (ClinVar SCV000166460, SCV000183970.11, SCV000211407.16, SCV000487372.2; 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, 38062336; 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). Although there is a suspicion that this variant may be associated with disease, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
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. -
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. -
This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -
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; internal data). 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). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Possibly Damaging". 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. -
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Hereditary cancer-predisposing syndrome Pathogenic:1Uncertain:2
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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. 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, 35668106; ClinVar SCV000166460, SCV000183970.11, SCV000487372.2; external laboratory communication). This variant has also been observed in biallelic individuals unaffected with colorectal cancer or polyposis (ClinVar SCV000166460, SCV000183970.11, SCV000211407.16, SCV000487372.2; 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, 38062336; 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). Although there is a suspicion that this variant may be associated with disease, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
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. -
not specified Uncertain:2
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 reports do not provide unequivocal conclusions about association of the variant with MUTYH-Associated Polyposis. Co-occurrences with other pathogenic variants 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). ClinVar contains an entry for this variant (Variation ID: 41764). Based on the evidence outlined above, the variant was classified as uncertain significance. -
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Gastric cancer;C3272841:Familial adenomatous polyposis 2 Pathogenic:1
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MUTYH-related disorder Uncertain:1
The MUTYH c.821G>A variant is predicted to result in the amino acid substitution p.Arg274Gln. The p.Arg274 residue of the MUTYH glycolase is located within the hallmark helix-hairpin-helix and Gly/Pro rich domain (HhH-GPD) and has been strictly conserved during evolution. This variant, also known as p.Arg260Gln in the literature, has been demonstrated to have reduced activity (both glycosylase and DNA binding) and has been reported in multiple individuals with primary sclerosing cholangitis (Forsbring et al. 2009. PubMed ID: 19443904), colonic polyps (Guarinos et al. 2014. PubMed ID: 24470512, reported as Arg247Gln) and colorectal cancer (Ali et al. 2008. PubMed ID: 18534194; Win et al. 2015. PubMed ID: 26202870). This variant is reported in 0.035% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has conflicting interpretations ranging from uncertain significance to pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/41764/). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at