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

gnomAD frequency: 0.00051  dbSNP: rs138089183

Total submissions: 21

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	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx	RCV000034682	SCV000211411	uncertain significance	not provided	2023-06-08	criteria provided, single submitter	clinical testing	Observed with MUTYH European founder variants, phase unknown, in individuals with phenotypes consistent with MAP at this laboratory and in the published literature as well as in individuals without MAP at an outside laboratory (Jones et al., 2009; ClinVar); Identified as homozygous in two individuals with colorectal cancer whose tumors demonstrated a mutational signature profile which was apparently not characteristic of biallelic MUTYH inactivation (Georgeson et al., 2022); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as Arg295Cys (c.883C>T) and Arg281Cys (c.841C>T); 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, 34426522, 33471991, 28135145, 28726808, 35668106, 35545820, 20816984, 16879101, 11160897, 11092888)
Invitae	RCV000198445	SCV000254716	uncertain significance	Familial adenomatous polyposis 2	2022-11-02	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	2023-08-11	criteria provided, single submitter	clinical testing	In the published literature, the variant has been reported in individuals affected with breast cancer (PMID: 33471991 (2021), 31159747 (2019)), pancreatic cancer (PMID: 28726808 (2018)), colorectal cancer (PMID: 28135145 (2017), 16408224 (2006), 12707038 (2003) 12606733 (2003)), MUTYH-associated polyposis (MAP) (PMID: 19732775 (2009)), and familial adenomatous polyposis (FAP) (PMID: 17949294 (2007)). Additionally, this variant has been observed in unaffected individuals (PMID: 33471991 (2021), 22703879 (2012)). Functional studies have reported conflicting accounts that this variant has no effect or a partial defect on MUTYH glycosylase activity and function (PMID: 20848659 (2010), 26377631 (2015), and 25820570 (2015)). The frequency of this variant in the general population, 0.001 (52/50772 chromosomes, http://gnomad.broadinstitute.org), is uninformative in 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 conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000212709	SCV000697714	uncertain significance	not specified	2023-10-10	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 (examples, Bhai_2021, deOliveira_2022, Bedics_2022, Aretz_2006, Niessen_2006, Halford_2003). Thus, 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). The following publications have been ascertained in the context of this evaluation (PMID: 16557584, 35545820, 34326862, 26377631, 28726808, 15465463, 20848659, 12707038, 22703879, 25820570, 27153395, 19032956, 16408224, 17949294, 22297469, 27829682, 27696107, 32615015, 12606733, 31159747, 19732775, 28135145, 35534704). 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=15), likely benign (n=1) and benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV003389675	SCV000806370	uncertain significance	MUTYH-related condition	2023-04-28	criteria provided, single submitter	clinical testing	The MUTYH c.925C>T variant is predicted to result in the amino acid substitution p.Arg309Cys. This variant has been identified in individuals with adenomatous polyposis and/or colorectal cancer; in some individuals a second MUTYH variant was also reported or an additional missense variant in PALB2 was identified (Supplementary Table 1, Jones et al. 2009. PubMed ID: 19394335; Supplementary Table 1, Vogt et al. 2009. PubMed ID: 19732775; Nielsen et al. 2009. PubMed ID: 19032956; Sieber et al. 2003. PubMed ID: 12606733; Table 2, Aretz et al. 2006. PubMed ID: 16557584; Subject 1095188515, Table S2, Yurgelun et al. 2015. PubMed ID: 25980754). At least one study identified this variant in individuals with a history of breast cancer, but also at an equal frequency in the unaffected control cohort (Out et al. 2012. PubMed ID: 22297469). Functional studies are conflicting regarding this variant’s impact on MUTYH function. Some studies have revealed this variant does not impact MUTYH glycosylase function in vitro (Table 1, Goto et al. 2010. PubMed ID: 20848659), while others have reported a decrease in enzyme activity, binding activity to damaged DNA, and impaired base excision repair activity (Komine et al. 2015. PubMed ID: 25820570; Brinkmeyer and David. 2015. PubMed ID: 26377631) and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from benign to uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/41765/). This variant is reported in 0.091% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-45797846-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
GeneKor MSA	RCV000131155	SCV000822081	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Mendelics	RCV003492336	SCV000837761	likely benign	Hereditary cancer	2024-01-23	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 Diagnostics, LLC DBA Color Health	RCV000131155	SCV000910575	benign	Hereditary cancer-predisposing syndrome	2016-06-22	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000198445	SCV001255471	uncertain significance	Familial adenomatous polyposis 2	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	likely benign	not provided	2022-05-01	criteria provided, single submitter	clinical testing	MUTYH: BP2, BS3:Supporting
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000034682	SCV002011052	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000198445	SCV002012379	uncertain significance	Familial adenomatous polyposis 2	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
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000212709	SCV002552506	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000198445	SCV002580791	uncertain significance	Familial adenomatous polyposis 2	2022-05-25	criteria provided, single submitter	clinical testing
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	Familial adenomatous polyposis 2		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	Familial adenomatous polyposis 2		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.