Submissions for variant NM_001048174.2(MUTYH):c.1063del (p.Ala357fs)

dbSNP: rs587778536

Total submissions: 32

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164291	SCV000214918	pathogenic	Hereditary cancer-predisposing syndrome	2024-08-05	criteria provided, single submitter	clinical testing	The c.1147delC pathogenic mutation, located in coding exon 12 of the MUTYH gene, results from a deletion of one nucleotide at nucleotide position 1147, causing a translational frameshift with a predicted alternate stop codon (p.A385Pfs*23). This alteration has been reported in a homozygous and compound heterozygous state in multiple individuals with polyposis and has been described as a European founder mutation (Eliason K et al. J. Med. Genet. 2005 Jan;42:95-6; Nielsen M et al. Gastroent. 2009 Feb;136:471-6; Pin E et al. Int. J. Cancer. 2013 Mar;132:1060-9; Ricci MT et al. J. Hum. Genet. 2017 Feb;62:309-315; Seguí N et al. Gut. 2015 Feb;64:355-6; Sieber OM et al. N. Engl. J. Med. 2003 Feb 27;348:791-9, Torrezan GT et al. Orphanet J Rare Dis. 2013 Apr;8:54; Vogt S et al. Gastroent. 2009 Dec;137:1976-85.e1-10). Functional studies indicate c.1147delC leads to a protein devoid of glycosylase and DNA binding activity (Ali M et al. Gastroent. 2008 Aug;135:499-507), as well as a 50-100% decrease in MUTYH protein expression levels compared to wild-type levels in a compound heterozygous state (Pin E et al. Int. J. Cancer. 2013 Mar;132:1060-9; Ruggieri V et al. Oncogene. 2013 Sep;32:4500-8). Of note, this alteration is also designated as c.1103delC, c.1105delC, and c.1145delC in published literature. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000196379	SCV000253862	pathogenic	Familial adenomatous polyposis 2	2025-01-26	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ala385Profs*23) in the MUTYH gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MUTYH are known to be pathogenic (PMID: 18534194, 20663686). This variant is present in population databases (rs587778536, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with multiple colorectal adenomas (PMID: 12606733, 19732775, 23108399, 23561487). This variant is also known as c.1103delC and c.1145delC. ClinVar contains an entry for this variant (Variation ID: 134860). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000235584	SCV000292629	pathogenic	not provided	2022-07-26	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19732775, 23507534, 23007840, 12606733, 31575519, 16557584, 22865608, 24691292, 18534194, 19032956, 20924129, 24728327, 27194394, 23108399, 20618354, 23561487, 28944238, 31589614, 34426522, 26556299, 31921681, 33827469, 30291343, 32088803, 33326660, 30787465, 33077847, 33134171, 30953464, 27829682)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000235584	SCV000601627	pathogenic	not provided	2017-03-23	criteria provided, single submitter	clinical testing
Counsyl	RCV000196379	SCV000678198	pathogenic	Familial adenomatous polyposis 2	2015-11-06	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000164291	SCV000685545	pathogenic	Hereditary cancer-predisposing syndrome	2023-04-03	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 12 of the MUTYH gene, creating a frameshift and premature translation stop signal. This variant is also known as c.1105delC, c.1103delC and c.1063delC in the literature. This variant is expected to result in an absent or non-functional protein product. Functional studies have found this variant to cause MUTYH protein instability and impaired DNA repair activities in carrier cells and abolished glycosylase and DNA binding activities in vitro (PMID: 15987719, 18534194. 23108399). This variant has been observed in multiple homozygous and biallelic carriers affected with polyposis and/or colorectal cancer (PMID: 12606733, 15635083, 16140997, 16557584, 17368238, 22266422, 22865608, 23561487, 27829682, 28502729, 35668106) and has been observed to segregate in 5 affected members of one Lynch syndrome family (PMID: 24691292). This variant has also been reported in an individual affected with a paranganglioma (PMID: 33748650). This variant has been identified in 18/281328 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MUTYH function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000626290	SCV000746949	likely pathogenic	Familial colorectal cancer	2017-12-18	criteria provided, single submitter	clinical testing
Mendelics	RCV000196379	SCV000837754	pathogenic	Familial adenomatous polyposis 2	2018-07-02	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000196379	SCV000915416	pathogenic	Familial adenomatous polyposis 2	2018-10-04	criteria provided, single submitter	clinical testing	The MUTYH c.1105delC (p.Ala371ProfsTer23) variant causes a frameshift, and is predicted to result in premature termination of the protein. Truncating variants in the MUTYH gene are known to be disease-causing. Across five studies as a representation of the available literature, the p.Ala371ProfsTer23 variant was identified in a total of 17 individuals with polyposis including sixteen in a compound heterozygous state and one in a homozygous state (Sieber et al. 2003; Nielsen et al. 2005; Aretz et al. 2006; Middeldorp et al. 2008; Laarabi et al. 2012). The variant was absent from 223 control subjects and is reported at a frequency of 0.001212 in the European American population of the Exome Sequencing Project. Functional studies demonstrate that the p.Ala371ProfsTer23 variant results in a truncated protein expressed at <1% of wild type levels which is completely devoid of glycosylase and DNA binding activities. These results are supported by position of the variant with respect to the domain structure of the protein where the variant is predicted to cause the loss of the catalytic domain of the enzyme (Ali et al. 2008; Ruggierie et al. 2013). Based on the collective evidence, the p.Ala371ProfsTer23 variant is classified as pathogenic for MYH-associated polyposis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000196379	SCV000917797	pathogenic	Familial adenomatous polyposis 2	2017-09-12	criteria provided, single submitter	clinical testing	Variant summary: The MUTYH c.1147delC (p.Ala385ProfsX23) variant results in a premature termination codon, predicted to cause a truncated or absent MUTYH protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g., c.1227_1228dupGG [p.Glu410fsX43] and c.1435G>T [p.Glu479X]). MutationTaster predicts a damaging outcome for this variant. This variant was found in 9/119682 control chromosomes at a frequency of 0.0000752, which does not exceed the estimated maximal expected allele frequency of a pathogenic MUTYH variant (0.0045644). The variant has been identified in numerous MAP patients, including homozygous family members (Vogt_2009). In addition, functional studies show that the variant is completely defective in glycosylase and DNA binding activities (Ali_2008). Multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000235584	SCV001248079	pathogenic	not provided	2021-10-01	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000235584	SCV001446530	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000235584	SCV002072205	pathogenic	not provided	2021-12-08	criteria provided, single submitter	clinical testing	DNA sequence analysis of the MUTYH gene demonstrated a single base pair deletion in exon 12, c.1147del. This pathogenic sequence change results in an amino acid frameshift and creates a premature stop codon 23 amino acids downstream of the change, p.Ala385Profs*23. This pathogenic sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated MUTYH protein with potentially abnormal function. Experimental studies have demonstrated that this sequence change impacts the function of the MUTYH protein (18534194, 15987719, 23108399). This sequence change has been described in the gnomAD database with a frequency of 0.011% in the Latino/admixed American subpopulation (dbSNP rs587778536). This pathogenic sequence change is a well-described pathogenic variant identified in multiple individuals in the homozygous and compound heterozygous state with MUTYH-associated polyposis (PMID: 19732775, 26556299, 27829682, 31921681, 28944238, 30291343, 12606733, 32088803, 30953464, 15635083, 16140997, 16557584, 17368238, 22266422, 22865608, 23561487). Based on these collective evidences, this sequence change is classified as pathogenic.
Sema4, Sema4	RCV000164291	SCV002532205	pathogenic	Hereditary cancer-predisposing syndrome	2021-05-30	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000235584	SCV002552499	pathogenic	not provided	2025-03-04	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000196379	SCV003807723	pathogenic	Familial adenomatous polyposis 2	2022-12-22	criteria provided, single submitter	clinical testing	ACMG classification criteria: PVS1 very strong, PS3 supporting, PM2 supporting, PM3 very strong
PreventionGenetics, part of Exact Sciences	RCV004530025	SCV004116135	pathogenic	MUTYH-related disorder	2023-10-09	criteria provided, single submitter	clinical testing	The MUTYH c.1147delC variant is predicted to result in a frameshift and premature protein termination (p.Ala385Profs*23). This is a well-documented recurrent variant among Europeans (Seguí et al. 2015. PubMed ID: 24691292) and has also been reported as c.1103delC in the literature among patients with MUTYH-associated polyposis (MAP), multiple colorectal adenomas and familial colorectal cancers (Sieber et al. 2003. PubMed ID: 12606733; Ali et al. 2008. PubMed ID: 18534194; Table S1, Vogt et al. 2009. PubMed ID: 19732775). In addition, in vitro functional studies have shown that this variant has reduced DNA binding activity (Ali et al. 2008. PubMed ID: 18534194), significantly affects protein stability (Parker et al. 2005 PubMed ID: 15987719), and also imposes oxidative stress, thus genetic instability (Ruggieri et al. 2013. PubMed ID: 23108399). This variant is reported in 0.011% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-45797371-AG-A). In ClinVar this variant is interpreted as pathogenic by the vast majority of labs (https://www.ncbi.nlm.nih.gov/clinvar/variation/134860/). Frameshift variants in MUTYH are expected to be pathogenic. This variant is interpreted as pathogenic.
Baylor Genetics	RCV000196379	SCV004198824	pathogenic	Familial adenomatous polyposis 2	2024-03-17	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000196379	SCV004842659	pathogenic	Familial adenomatous polyposis 2	2024-09-03	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 12 of the MUTYH gene, creating a frameshift and premature translation stop signal. This variant is also known as c.1105delC, c.1103delC and c.1063delC in the literature. This variant is expected to result in an absent or non-functional protein product. Functional studies have found this variant to cause MUTYH protein instability and impaired DNA repair activities in carrier cells and abolished glycosylase and DNA binding activities in vitro (PMID: 15987719, 18534194. 23108399). This variant has been observed in multiple homozygous and biallelic carriers affected with polyposis and/or colorectal cancer (PMID: 12606733, 15635083, 16140997, 16557584, 17368238, 22266422, 22865608, 23561487, 27829682, 28502729, 35668106) and has been observed to segregate in 5 affected members of one Lynch syndrome family (PMID: 24691292). This variant has also been reported in an individual affected with a paranganglioma (PMID: 33748650). This variant has been identified in 18/281328 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MUTYH function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000196379	SCV004848004	pathogenic	Familial adenomatous polyposis 2	2019-12-11	criteria provided, single submitter	clinical testing	The p.Ala385fs variant in MUTYH has been reported in >20 individuals (1 homozygote and >20 compound heterozygotes) with MUTYH-related attenuated familial adenomatous polyposis (FAP) and segregated with disease in >6 affected relatives from 4 families (Nielsen 2009, Vogt 2009, Pin 2013, Torrezan 2013, Ruggieri 2013). It has also been identified in 0.01% (4/35430) of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org) and has been reported in ClinVar (Variation ID: 134860). In vitro functional studies provide some evidence that the p.Ala385fs variant may impact protein function (Pin 2013, Ruggieri 2013). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 385 and leads to a premature termination codon 23 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Homozygous loss of function of the MUTYH gene is an established disease mechanism in individuals with MUTYH-related attenuated FAP. In summary, this variant meets our criteria to be classified as pathogenic for MUTYH-related attenuated FAP in an autosomal recessive manner. ACMG/AMP Criteria applied: PVS1, PM3_VeryStrong, PP1_Strong.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000235584	SCV005199294	pathogenic	not provided	2022-05-27	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005016419	SCV005653029	pathogenic	Familial adenomatous polyposis 2; Gastric cancer	2024-05-14	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000235584	SCV005879779	pathogenic	not provided	2024-11-08	criteria provided, single submitter	clinical testing	The MUTYH c.1147del; p.Ala385ProfsTer23 variant (rs587778536), also known as 1105del, is reported in the literature in multiple individuals with MUTYH-associated polyposis (see Nielsen 2005, Sieber 2003, Sommer 2022, Vogt 2009). This variant is also reported in ClinVar (Variation ID: 134860). It is observed in the general population with an overall allele frequency of 0.006% (18/281328 alleles) in the Genome Aggregation Database. This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Nielsen M et al. Multiplicity in polyp count and extracolonic manifestations in 40 Dutch patients with MYH associated polyposis coli (MAP). J Med Genet. 2005 Sep;42(9):e54. PMID: 16140997. Sieber OM et al. Multiple colorectal adenomas, classic adenomatous polyposis, and germ-line mutations in MYH. N Engl J Med. 2003 Feb 27;348(9):791-9. PMID: 12606733. Sommer AK et al. Solving the genetic aetiology of hereditary gastrointestinal tumour syndromes- a collaborative multicentre endeavour within the project Solve-RD. Eur J Med Genet. 2022 May;65(5):104475. PMID: 35283344. Vogt S et al. Expanded extracolonic tumor spectrum in MUTYH-associated polyposis. Gastroenterology. 2009 Dec;137(6):1976-85.e1-10. PMID: 19732775.
ITMI	RCV000121593	SCV000085789	not provided	not specified	2013-09-19	no assertion provided	reference population
Pathway Genomics	RCV000144632	SCV000189959	pathogenic	Carcinoma of colon	2014-07-24	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000144632	SCV000592709	pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	The MUTYH p.Ala385Profsx23 deletion variant was identified in 51 of 1892 proband chromosomes (frequency: 0.027) from individuals or families with adenomatous polyposis or colon cancer (Aretz 2006, Nielsen 2009, Ruggieri 2013, Sieber 2003, Vogt 2009). Of these probands, two individuals were homozygous for the variant and the remaining individuals were compound heterozygotes, harbouring a second MUTYH variant. The variant was previously identified by our laboratory in three individuals with adenomatous polyposis. The variant was also identified in HGMD, the “InSiGHT Colon Cancer Database”, and the ClinVar database (submitted by Inova Translational Medicine Institute, clinical significance not provided). The p.Ala385Profsx23 deletion variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 385 and leads to a premature stop codon 23 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants in the MUTYH gene are an established mechanism of disease in MUTYH-associated polyposis. In addition, a cell line with the variant showed decreased levels of transcript and protein (Ruggieri 2013), and an in vitro study found that the variant protein had a lower molecular weight than wild-type protein and was devoid of glycosylase and DNA binding activities (Ali 2008). In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.
GeneReviews	RCV000196379	SCV001167334	not provided	Familial adenomatous polyposis 2		no assertion provided	literature only	Common in northern European populations
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000235584	SCV001741659	pathogenic	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000235584	SCV001797625	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000235584	SCV001924915	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000235584	SCV001969845	pathogenic	not provided		no assertion criteria provided	clinical testing
Solve-RD Consortium	RCV000196379	SCV005200022	likely pathogenic	Familial adenomatous polyposis 2	2022-06-01	no assertion criteria provided	provider interpretation	Variant confirmed as disease-causing by referring clinical team