ClinVar Miner

Submissions for variant NM_001048174.2(MUTYH):c.841C>T (p.Arg281Cys)

gnomAD frequency: 0.00061  dbSNP: rs138089183
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Total submissions: 20
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131155 SCV000186097 likely benign Hereditary cancer-predisposing syndrome 2018-08-28 criteria provided, single submitter clinical testing In silico models in agreement (benign) ;Other data supporting benign classification
GeneDx RCV000034682 SCV000211411 uncertain significance not provided 2022-05-31 criteria provided, single submitter clinical testing Observed with MUTYH European founder variants, phase unknown, in individuals with phenotypes consistent with pathogenic biallelic variants in this gene at this laboratory and in the published literature and in individuals without MUTYH-associated polyposis at an outside laboratory (Jones 2009, ClinVar SCV000186097.7); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23507534, 24252905, 16408224, 22297469, 16557584, 20848659, 25820570, 25980754, 21235684, 27829682, 31159747, 25318351, 22703879, 12606733, 12707038, 17949294, 19032956, 19732775, 26377631, 19394335, 27696107, 23605219, 27153395, 28087410, 28108460, 19527492, 15465463, 29684080, 32615015, 20816984, 16879101, 11160897, 11092888, 34426522)
Invitae RCV000198445 SCV000254716 uncertain significance MUTYH-related attenuated familial adenomatous polyposis 2021-12-17 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 309 of the MUTYH protein (p.Arg309Cys). This variant is present in population databases (rs138089183, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with denomatous polyps and colorectal cancer, and breast cancer (PMID: 12606733, 12707038, 16408224, 16557584, 17949294, 19032956, 19394335, 19732775, 22297469; 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 c.883C>T (Arg295Cys) and c.841C>T (Arg281Cys). ClinVar contains an entry for this variant (Variation ID: 41765). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Experimental studies have shown that this missense change does not substantially affect MUTYH function (PMID: 20848659, 26377631). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000034682 SCV000601662 uncertain significance not provided 2020-12-03 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000212709 SCV000697714 uncertain significance not specified 2022-05-08 criteria provided, single submitter clinical testing Variant summary: MUTYH c.925C>T (p.Arg309Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00048 in 254474 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MUTYH causing MUTYH-Associated Polyposis (0.00048 vs 0.0046), allowing no conclusion about variant significance. c.925C>T has been reported in the literature spanning years 2003-2020 among individuals affected with APC-negative adenomatous polyposis, colorectal cancer and other tumor phenotypes without strong evidence for causality. Thus, these report(s) do not provide unequivocal conclusions about association of the variant with MUTYH-associated Polyposis. These report(s) do not provide unequivocal conclusions about association of the variant with MUTYH-Associated Polyposis. Several publications have reported conflicting experimental evidence evaluating an impact on protein function. Multiple studies showed discordant results for adenine glycosylase activity with values similar to the wild-type enzyme (Goto_2010) while another report demonstrated low fractions of active enzyme, compromised affinity for damaged DNA and reduced rates for adeninine excision (Brinkmeyer_2015). The variant did not affect binding of MUTYH with the Hus1 subunit of the 9-1-1 heterotrimeric complex, Rad9-Hus1-Rad1, which is thought to stimulate the glycosylase activity of the protein (Brinkmeyer_2015). Lastly, a complementation assay evaluating the functional deficiency in the E Coli by monitoring spontaneous mutation rates showed a partially defective activity (Komine_2015). Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation citing conflicting assessments namely VUS (n=12), likely benign (n=1) and benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
PreventionGenetics,PreventionGenetics RCV000034682 SCV000806370 uncertain significance not provided 2017-12-21 criteria provided, single submitter clinical testing
GeneKor MSA RCV000131155 SCV000822081 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Mendelics RCV000198445 SCV000837761 uncertain significance MUTYH-related attenuated familial adenomatous polyposis 2018-07-02 criteria provided, single submitter clinical testing
Eurofins NTD LLC (GA) RCV000034682 SCV000859723 uncertain significance not provided 2018-02-27 criteria provided, single submitter clinical testing
Color Health, Inc RCV000131155 SCV000910575 benign Hereditary cancer-predisposing syndrome 2016-06-22 criteria provided, single submitter clinical testing
Illumina Laboratory Services,Illumina RCV000198445 SCV001255471 uncertain significance MUTYH-related attenuated familial adenomatous polyposis 2018-03-08 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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
CeGaT Center for Human Genetics Tuebingen RCV000034682 SCV001748142 uncertain significance not provided 2021-03-01 criteria provided, single submitter clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden RCV000198445 SCV002011052 uncertain significance MUTYH-related attenuated familial adenomatous polyposis 2021-11-03 criteria provided, single submitter clinical testing
St. Jude Clinical Genomics Lab, St. Jude Children's Research Hospital RCV000198445 SCV002012379 uncertain significance MUTYH-related attenuated familial adenomatous polyposis 2021-08-10 criteria provided, single submitter clinical testing The MUTYH c.925C>T (p.Arg309Cys) missense change has a maximum subpopulation frequency of 0.091% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/1-45797846-G-A). Both in silico tools and functional assays are not in agreement about the effect of this variant on protein function. Functional studies have demonstrated a significant decrease in enzyme activity, impaired binding affinity to damaged DNA, and reduced rates of base excision repair (PMID: 26377631), as well as glycosylase activity similar to the wildtype (PMID: 20848659). A complementation assay evaluating functional deficiency in E.coli showed partially defective activity based on spontaneous mutation rates (PMID: 25820570). This variant has been reported in one individual with 10-20 colorectal polyps at age 58 and without colorectal cancer who was compound heterozygous for this variant and the pathogenic p.Tyr179Cys (PM3; PMID: 19732775). It has also been reported in individuals with MUTYH-associated polyposis or referred for cancer genetic testing (PMID: 19032956, 27153395, 31159747) as well as in control individuals (PMID: 22703879). This variant is also known as c.883C>T (Arg295Cys) and c.841C>T (Arg281Cys) in the literature. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PM3.
Genetic Services Laboratory,University of Chicago RCV000212709 SCV002067665 uncertain significance not specified 2021-11-05 criteria provided, single submitter clinical testing DNA sequence analysis of the MUTYH gene demonstrated a sequence change, c.925C>T, in exon 10 that results in an amino acid change, p.Arg309Cys. This sequence change has been described in the gnomAD database with a frequency of 0.09% in the European population (dbSNP rs138089183). The p.Arg309Cys change affects a poorly conserved amino acid residue located in a domain of the MUTYH protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Arg309Cys substitution. The c.925C>T sequence change has been identified in individuals with colorectal polyps and/or colorectal cancer (PMIDs: 19732775; 19527492, 27829682). Out et al., 2012, identified the p.Arg309Cys change in individuals with a personal and/or family history of breast cancer and in controls, without a statistically significant difference in the rates of detection between the two populations (PMID: 22297469). In vitro analyses of the p.Arg309Cys change have shown contradictory results. Goto et al., 2010, demonstrated that the variant retains normal glycosylase activity in vitro (PMID: 20848659). However, Brinkmeyer et al., 2015, and Komine et al., 2015, performed in vitro assays that demonstrated significant decreases in enzyme activity, binding activity to damaged DNA, and defective base excision repair activity (PMIDs: 26377631, 25820570). Due to these contrasting evidences, the clinical significance of the p.Arg309Cys change remains unknown at this time.
Sema4,Sema4 RCV000131155 SCV002532343 uncertain significance Hereditary cancer-predisposing syndrome 2022-02-15 criteria provided, single submitter curation
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034682 SCV000043374 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 RCV000198445 SCV001553145 uncertain significance MUTYH-related attenuated familial adenomatous polyposis no assertion criteria provided clinical testing The MUTYH p.Arg309Cys variant was identified in 11 of 6552 proband chromosomes (frequency: 0.002) from individuals or families with MAP, colorectal cancer, or breast cancer and was present in 9 of 3332 control chromosomes (frequency: 0.003) from healthy individuals (Aretz 2006, Halford 2003, Jones 2009, Nielsen 2009, Olschwang 2007, Out 2012, Rohlin 2017, Sieber 2003, Vogt 2009). Note that the variant was identified as c.883C>T (NM_001048171.1), p.Arg295Cys (NP_001041636.1) and p.Arg281Cys (NP_001041638.1) in the literature (Goto 2010, Komine 2015, Brinkmeyer 2015). The variant was also identified in dbSNP (ID: rs138089183) as "With Uncertain significance allele", and in ClinVar (classified as likely benign by Ambry Genetics; as uncertain significance by GeneDx, Invitae, and three clinical laboratories). The variant was not identified in COGR, Cosmic, or the UMD-LSDB database. The variant was identified in control databases in 129 of 277082 chromosomes at a frequency of 0.0005 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 1 of 24006 chromosomes (freq: 0.00004), Other in 5 of 6466 chromosomes (freq: 0.0008), Latino in 4 of 34414 chromosomes (freq: 0.0001), European in 115 of 126606 chromosomes (freq: 0.0009), Finnish in 3 of 25792 chromosomes (freq: 0.0001), and South Asian in 1 of 30780 chromosomes (freq: 0.00003); it was not observed in the Ashkenazi Jewish, or East Asian populations. The p.Arg309 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. The variant exhibited low levels of active enzyme (5%) compared to WT MUTYH and displayed a significant decrease in substrate binding affinity relative to the WT enzyme (Brinkmeyer 2015). In addition, in an in vitro glycosylase assay two studies displayed the variant having normal glycosylase activity (Goto 2010, Komine 2015) but a third showed that glycosylase activity was less efficient (Brinkmeyer 2015). 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 RCV000198445 SCV001749417 not provided MUTYH-related attenuated familial adenomatous polyposis no assertion provided phenotyping only Variant interpreted as Uncertain significance and reported on 05-19-2020 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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV000212709 SCV002552506 uncertain significance not specified 2022-01-18 no assertion criteria provided clinical testing

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