ClinVar Miner

Submissions for variant NM_001048174.2(MUTYH):c.737G>A (p.Arg246Gln) (rs149866955)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000123156 SCV000166460 likely pathogenic MYH-associated polyposis 2020-10-20 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 274 of the MUTYH protein (p.Arg274Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs149866955, ExAC 0.04%). This variant has been observed in individual(s) with clinical features of MUTYH-associated polyposis (PMID: 11818965, 24444654, 19245865, 29458332, 27829682, Invitae). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 41764). This variant has been reported to affect MUTYH protein function (PMID: 18534194, 19443904). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics RCV000129219 SCV000183970 likely pathogenic Hereditary cancer-predisposing syndrome 2020-06-10 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 known (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 1 of 34 unrelated individuals considered high-risk for colorectal cancer who did not carry pathogenic variants in mismatch repair genes (Dominguez-Valentin M et al. BMC Med. Genet. 2018 Feb;19:26). 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). Another missense alteration affecting the same amino acid, p.R274W (also known as p.R260W), has been reported in conjunction with two different pathogenic MUTYH mutations in Italian and German patients with MUTYH-Associated Polyposis syndrome (Aceto G et al. Hum. Mutat. 2005 Oct;26:394; Aretz S et al. Int. J. Cancer. 2006 Aug;119:807-14; Vogt S et al. Gastroenterology. 2009 Dec;137:1976-85.e1-10; Aceto GM et al. J. Exp. Clin. Cancer Res. 2015 Oct;34:131). This similar alteration was also reported to have defective repair activity and reduced protein expression (Komine K et al. Hum. Mutat. 2015 Jul;36:704-11). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Of note, this alteration is also designated as p.R260Q (c.779G>A) in published literature. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
GeneDx RCV000034681 SCV000211407 uncertain significance not provided 2018-08-21 criteria provided, single submitter clinical testing This variant is denoted MUTYH c.821G>A at the cDNA level, p.Arg274Gln (R274Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGG>CAG). This variant, also known as Arg260Gln using an alternate transcript, has been observed in the compound heterozygous state with a pathogenic MUTYH variant in one individual for whom the clinical history was not reported (Win 2014). It has also been observed in the single heterozygous state in individuals with colorectal cancer and/or polyps as well as breast, prostate, and other cancers (Cleary 2009, Tung 2016, Mandelker 2017, Ricci 2017). Functional studies have demonstrated reduced but partially retained glycosylation (Ali 2008, Forsbring 2009). MUTYH Arg274Gln was observed at an allele frequency of 0.04% (45/125,728) in individuals of European ancestry in large population cohorts (Lek 2016). This variant is located in the APE1 binding domain (Parker 2001, Yang 2001). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MUTYH Arg274Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. Of note, MUTYH-Associated Polyposis (MAP) is a recessive condition associated with two MUTYH pathogenic variants on opposite chromosomes.
Counsyl RCV000123156 SCV000487372 uncertain significance MYH-associated polyposis 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 2020-11-25 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 expected 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-occuring MSH2 pathogenic variants (Win_2015), 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. The specific co-occurrences with other pathogenic variant(s) mentioned above include, ATM c.170G>A, p.Trp57X (Bunnell_2017); MSH2 c.136_164del, p.His46GlyfsTer26 (Win_2015), providing supporting evidence for a benign role due to an alternative molecular basis of disease. 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. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Some submitters cite overlapping evidence utilized in the context of this evaluation but do not allude to the pathogenic co-occurrences ascertained herein. Based on the evidence outlined above, the variant retained its classification as uncertain significance.
Laboratory for Molecular Medicine, Partners HealthCare 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, 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,PreventionGenetics RCV000034681 SCV000806368 uncertain significance not provided 2017-05-04 criteria provided, single submitter clinical testing
Color Health, Inc RCV000129219 SCV000902654 uncertain significance Hereditary cancer-predisposing syndrome 2020-11-24 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 in the literature. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Another variant at this position (p.Arg274Trp) is consistently classified as Likely Pathogenic suggesting the position is important for function (ClinVar Variation ID: 449417). 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 one biallelic individual affected with colorectal cancer (PMID: 24444654; MUTYH p.Gly396Asp) and in heterozygous in individuals suspected or diagnosed with colorectal cancer or polyposis (PMID: 11818965, 19245865, 24444654, 24470512, 26202870, 27829682, 28873162, 29458332). This variant has also been observed in unaffected controls (PMID: 19245865, 22703879) and in some affected individuals who also carried pathogenic variants in other genes that may 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). 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 uncertain significance not provided 2019-04-09 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000123156 SCV001255472 uncertain significance MYH-associated polyposis 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.
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 MYH-associated polyposis no assertion provided phenotyping only Variant interpreted as Likely pathogenic and reported on 06-11-2020 by Invitae. 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.

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