Submissions for variant NM_001048174.2(MUTYH):c.1192C>T (p.Arg398Cys)

gnomAD frequency: 0.00081  dbSNP: rs150792276

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000034670	SCV000149665	likely benign	not provided	2021-06-10	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 16134147, 25980754, 30564557, 22703879, 24470512, 16557584, 19531215, 14991577, 22976915, 25820570, 20687945, 21777424, 17524638, 25569433, 27829682, 26976419, 25862857, 27621404, 27498913, 26898890, 16616356, 28944238, 31159747, 33383211, 23108399)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000119122	SCV000153836	likely benign	Familial adenomatous polyposis 2	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000115756	SCV000172769	likely benign	Hereditary cancer-predisposing syndrome	2019-04-27	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000034670	SCV000601632	uncertain significance	not provided	2022-09-09	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.0022 (26/11602 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, this variant has been identified in multiple individuals and families affected with various cancers including colorectal cancer (PMID: 28944238 (2017), 30256826 (2018), 30850667 (2019)), colorectal polyposis (PMID: 24470512 (2014), 25980754 (2015), 27829682 (2016)), breast and/or ovarian cancer (PMID: 30564557 (2018), 31159747 (2019), 31921681 (2019)), endometrial cancer (PMID: 27443514 (2016)), pancreatic cancer (PMID: 30151275 (2018)), and lung cancer (PMID: 14991577 (2004)). It has also been found in unaffected individuals (PMID: 16616356 (2006)). An in vitro functional study reports this variant does not have a significant effect MUTYH protein activity, however, this variant’s effect on MUTYH glycosylase activity was not assessed (PMID: 25820570 (2015)). 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	RCV000212715	SCV000697674	likely benign	not specified	2024-06-24	criteria provided, single submitter	clinical testing	Variant summary: MUTYH c.1276C>T (p.Arg426Cys) results in a non-conservative amino acid change located in the NUDIX hydrolase domain (IPR000086) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00081 in 252980 control chromosomes, predominantly at a frequency of 0.0014 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in MUTYH causing MUTYH-Associated Polyposis (0.00081 vs 0.0046), allowing no conclusion about variant significance. c.1276C>T has been reported in multiple FAP or attenuated FAP patients in monoallelic state (e.g. Aceto_2005, Aretz_2006, de Lyon_2013, Ricci_2017, Sulova_2009). Furthermore, it has been reported with other pathogenic MUTYH variants in biallelic patients affected with synchronous/metachronous polyps (Lopez-Villar_2010) and colorectal cancer (e.g. De Rycke 2017, Yurgelun 2017). In some of these reports, it was classified as a VUS in settings of multigene cancer panel testing. Additional reports of the variant in individuals with a personal and/or family history of colorectal cancer, HBOC, lung and endometrial cancer have also been published (e.g. Fleischmann_2004, Ricci_2016, Ring_2016, Tung_2016, Martin-Morales_2018, Rizzolo_2018, Oliver_2019, Lin_2019, Tsaousis_2019, Grasel_2020, Pope_2021, Sahin_2022). These data do not allow any conclusion about variant significance. Multiple co-occurrences with other pathogenic variant(s) have been observed at our laboratory (BRCA2 c.4647_4650delAGAG , p.Lys1549fsX18 ; APC c.2161_2170delGGAAGTGCTG, p.Gly721fsX3; MSH6 c.3013C>T, p.Arg1005X; PALB2 c.2386G>T, p.Gly796X), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant as evidenced by comparable function to wild-type in terms of suppression of spontaneous mutations (Komine_2015). The following publications have been ascertained in the context of this evaluation (PMID: 22703879, 25820570, 16134147, 16557584, 19531215, 24470512, 20687945, 17524638, 14991577, 26976419, 22976915, 27443514, 28135145, 28944238, 30256826, 30151275, 27829682, 30564557, 30850667, 31159747, 31921681, 31422818, 33383211, 33134171, 35089076, 35430768, 35628513). ClinVar contains an entry for this variant (Variation ID: 41753). Based on the evidence outlined above, the variant was classified as likely benign.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000212715	SCV000711723	uncertain significance	not specified	2017-01-11	criteria provided, single submitter	clinical testing	The p.Arg426Cys variant in MUTYH has been reported in at > 8 individuals with co lorectal cancer (Aceto 2005, Aretz 2006, Sulova 2007, Gomez-Fernadez 2009, Lopez -Villar 2010, Guarinos 2014, Yurgelun 2015, Ricci 2017), 2 individuals with brea st cancer (Tung 2016), 1 individual with lung cancer (Al-Tassan 2004) and has a lso been reported by other clinical laboratories in ClinVar (Variation ID 41753) . All individuals reported in the literature were heterozygous and did not carry a second MUTYH variant. This variant has also been identified in 0.1% (184/1266 06) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Althou gh this variant has been seen in the general population, its frequency is not hi gh enough to rule out a pathogenic role. In vitro functional studies provide som e evidence that the p.Arg426Cys variant may not impact protein function (Komine 2015) and computational prediction tools and conservation analysis suggest that the p.Arg426Cys variant may not impact the protein, though this information is n ot predictive enough to rule out pathogenicity. In summary, the clinical signifi cance of the p.Arg426Cys variant is uncertain. ACMG/AMP Criteria applied: BP4.
GeneKor MSA	RCV000115756	SCV000822073	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Mendelics	RCV003492335	SCV000837748	likely benign	Hereditary cancer	2024-01-23	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000212715	SCV000885747	likely benign	not specified	2018-08-29	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115756	SCV000902581	likely benign	Hereditary cancer-predisposing syndrome	2016-11-07	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000119122	SCV001253576	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.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000034670	SCV002011069	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000212715	SCV002067654	uncertain significance	not specified	2022-01-04	criteria provided, single submitter	clinical testing	DNA sequence analysis of the MUTYH gene demonstrated a sequence change, c.1276C>T, in exon 13 that results in an amino acid change, p.Arg426Cys. This sequence change has been described in the gnomAD database with a frequency of 0.15% in the non-Finnish European sub-population (dbSNP rs150792276). The p.Arg426Cys change affects a poorly conserved amino acid residue located in a domain of the MUTYH protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Arg426Cys substitution. The p.Arg426Cys sequence change has been reported in the heterozygous state in multiple individuals with colorectal cancer (PMIDs: 16134147, 16557584, 17524638, 19531215, 20687945, 24470512, 25980754), two individuals with breast cancer (PMID: 26976419), and one individual with lung cancer (PMID: 14579148). Functional studies using a yeast complementation assay demonstrated that MUTYH p.Arg426Cys had base excision repair activity similar to wild-type (PMID: 25820570). Due to these contrasting evidences, the clinical significance of the p.Arg426Cys change remains unknown at this time.
Mayo Clinic Laboratories, Mayo Clinic	RCV000034670	SCV002542097	uncertain significance	not provided	2021-06-07	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000212715	SCV002552418	uncertain significance	not specified	2024-07-31	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000119122	SCV002580500	uncertain significance	Familial adenomatous polyposis 2	2022-03-25	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000119122	SCV003928044	uncertain significance	Familial adenomatous polyposis 2	2023-06-02	criteria provided, single submitter	clinical testing	The MUTYH c.1276C>T (p.Arg426Cys) missense change has a maximum subpopulation frequency of 0.15% in gnomAD v2.1.1 and is reported to be homozygous in one individual (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, however a functional assay in E.coli showed that glycosylase repair activity was comparable to the wildtype (PMID: 25820570). This variant has been reported as homozygous in individuals with familial adenomatous polyposis that reportedly did not harbor pathogenic variants in APC (PMID: 16134147, 16557584, 19531215, 20687945). It has also been reported to co-occur with a pathogenic MUYTH pathogenic variant in two individuals with ≥10 adenomas, where one of these individuals also had a personal and family history of colorectal cancer (PMID: 20687945). In addition, this variant has been reported as heterozygous in individuals with familial adenomatous polyposis (PMID: 17524638, 20687945, 22976915, 24470512), colorectal cancer (PMID: 28135145, 28944238, 30256826, 30850667), breast cancer (PMID: 26976419, 30564557), pancreatic cancer (PMID: 30151275), and endometrial cancer (PMID: 27443514). This variant is also known as p.Arg412Cys in the literature. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034670	SCV000043368	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.
Pathway Genomics	RCV000144640	SCV000189967	uncertain significance	Carcinoma of colon	2014-07-24	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000144640	SCV000592715	uncertain significance	Carcinoma of colon		no assertion criteria provided	clinical testing	The MUTYH p.Arg426Cys variant was identified in 15 of 6049 proband chromosomes (frequency: 0.003) from individuals or families with FAP, MAP, early onset colorectal cancer or breast cancer and was present in 1 of 1152 control chromosomes (frequency: 0.001) from healthy individuals (Lopez-Villar 2010, Fleischmann 2004, Aceto 2005, Aretz 2006, Kanter-Smoler 2006, Guarinos 2014, DeRycke 2017, Ricci 2017, Tung 2016). In functional complementation tests using E. coli and monitoring spontaneous mutation rates, the variant was found to be functionally retained (Komine 2015). The variant was also identified in dbSNP (ID: rs150792276) as "With Uncertain significance allele", ClinVar (classified as likely benign by Invitae and Ambry Genetics; as uncertain significance by GeneDx and nine other submitters) and in UMD (8x as an unvalidated variant). In UMD the variant was identified with co-occurring pathogenic MUTYH variants c.1145G>A, p.Gly382Asp and c.692G>A, p.Arg231His. The variant was also identified by our laboratory in 5 individuals with colon cancer (no co-occurrence with a pathogenic variant). The variant was identified in control databases in 226 of 277022 chromosomes (1 homozygous) at a frequency of 0.0008 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 8 of 24010 chromosomes (freq: 0.0003), Other in 7 of 6454 chromosomes (freq: 0.001), Latino in 8 of 34418 chromosomes (freq: 0.0002), European in 184 of 126606 chromosomes (freq: 0.001), East Asian in 19 of 18866 chromosomes (freq: 0.001); it was not observed in the Ashkenazi Jewish, Finnish, and South Asian populations. The p.Arg426 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 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.
True Health Diagnostics	RCV000115756	SCV000788062	uncertain significance	Hereditary cancer-predisposing syndrome	2017-09-28	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004528163	SCV000806341	likely benign	MUTYH-related disorder	2024-05-14	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).