Submissions for variant NM_001048174.2(MUTYH):c.849+3A>C

gnomAD frequency: 0.00013  dbSNP: rs587780751

Total submissions: 26

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000123158	SCV000166462	pathogenic	Familial adenomatous polyposis 2	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change falls in intron 10 of the MUTYH gene. It does not directly change the encoded amino acid sequence of the MUTYH protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs587780751, gnomAD 0.01%). This variant has been observed in individual(s) with adenomatous polyposis (PMID: 12853198, 16616356, 19732775, 22773231, 22865608). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It is commonly reported in individuals of North-Eastern Italy ancestry (PMID: 12853198, 16616356, 19732775, 22773231, 22865608). This variant is also known as c.891+3A>C. ClinVar contains an entry for this variant (Variation ID: 135992). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 10 and introduces a premature termination codon (PMID: 16616356, 22865608; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000129539	SCV000184317	pathogenic	Hereditary cancer-predisposing syndrome	2024-02-16	criteria provided, single submitter	clinical testing	The c.933+3A>C intronic alteration results from an A to C substitution 3 nucleotides after coding exon 10 of the MUTYH gene. Based on data from gnomAD, the C allele has an overall frequency of 0.007% (21/282792) total alleles studied. The highest observed frequency was 0.014% (18/129140) of European (non-Finnish) alleles. This alteration has been well described in the literature, and has been reported in both the homozygous and compound heterozygous state with other MUTYH alterations in multiple individuals with MUTYH-associated polyposis (Vogt, 2009; Urso, 2013; Ricci, 2017; Sutcliffe, 2019; Daans, 2020; Ambry internal data). This alteration has also been described as a founder mutation in the Northeastern Italian and German populations (Pin, 2013). Of note, this alteration is also designated as c.891+3A>C in published literature. This nucleotide position is poorly conserved in available vertebrate species. RNA studies have demonstrated this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the available evidence, this alteration is classified as pathogenic.
GeneDx	RCV000212711	SCV000211413	pathogenic	not provided	2021-12-22	criteria provided, single submitter	clinical testing	Splice site variant demonstrated to result in exon 10 skipping in a gene for which loss-of-function is a known mechanism of disease (Kanter-Smoler 2006, Pin 2013); Published functional studies demonstrate a damaging effect: defects in glycosylase activity (Ruggieri 2013); This variant is associated with the following publications: (PMID: 20618354, 30233642, 30604180, 12853198, 26202870, 25980754, 23108399, 22865608, 19732775, 27194394, 26798439, 27829682, 26446593, 27799157, 23891399, 16616356, 16140997, 18495334, 22976915, 29406563, 22773231, 31277343, 32088803, 33258288, 30787465, 33606809, 34026625, 34704405, 34485163)
Eurofins Ntd Llc (ga)	RCV000212711	SCV000331108	pathogenic	not provided	2015-07-09	criteria provided, single submitter	clinical testing
Counsyl	RCV000123158	SCV000487342	pathogenic	Familial adenomatous polyposis 2	2016-03-18	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129539	SCV000537683	pathogenic	Hereditary cancer-predisposing syndrome	2023-04-11	criteria provided, single submitter	clinical testing	This variant causes an A to C nucleotide substitution at the +3 position of intron 10 of the MUTYH gene. Functional RNA studies have shown that this variant causes skipping of exon 10, resulting in a frameshift and premature stop codon (p.Gly264Trpfs*7) (PMID: 16616356, 22865608). This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with MUTYH-associated polyposis as homozygous or in trans with another pathogenic variant (PMID: 12853198, 16616356, 18495334, 19732775, 20618354, 22773231, 22865608, 23108399, 27829682), colorectal cancer (PMID: 28135145, 29478780, 35668106), breast cancer (PMID: 30564557, 33606809), or pancreatic ductal adenocarcinoma (PMID: 34506673). This variant is considered a founder mutation in Western Europe (PMID: 22865608). This variant has been identified in 21/282792 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000123158	SCV000697716	pathogenic	Familial adenomatous polyposis 2	2016-02-08	criteria provided, single submitter	clinical testing	Variant summary: MUTYH c.933+3A>C variant affects a non-conserved intronic nucleotide. Mutation Taster predicts a damaging outcome for this variant, and 5/5 Alamut algorithms predict the variant to alter normal splicing, which is supported by patient cDNA showing that this variant results in a fusion of exon 9 to exon 11. This variant is found in 8/124162 control chromosomes at a frequency of 0.0000644, which does not significantly exceed maximal expected frequency of a pathogenic allele (0.0055902). However, the variant has been cited in numerous CRC patients in the literature. In addition, several diagnostic clinical laboratories and databases classified this variant as pathogenic. Taken together, this is a disease variant and was classified as pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000123158	SCV000711785	pathogenic	Familial adenomatous polyposis 2	2019-12-11	criteria provided, single submitter	clinical testing	The c.933+3A>C variant in MUTYH has been previously reported in 24 individuals (23 were compound heterozygotes, 1 was a homozygote, and 1 was a heterozygote) with MUTYH-related attenuated familial adenomatous polyposis (FAP)and segregated with disease in 7 affected family members (Sampson 2003, Vogt 2009, Pin 2013). It has also been identified in 0.01% (18/129140) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org).This frequency is low enough to be consistent with the carrier frequency of MUTYH-related attenuated FAP in the general population. This variant is located in the 5' splice region. Computational tools do suggest an impact to splicing and functional studies provide evidence that this variant alters splicing (Pin 2013). In summary, this variant meets criteria to be classified as pathogenic for FAP in an autosomal recessive manner. ACMG/AMP Criteria applied: PM3_VeryStrong, PP1_Strong, PS3_Moderate, PP3.
Mendelics	RCV000123158	SCV000837759	pathogenic	Familial adenomatous polyposis 2	2018-07-02	criteria provided, single submitter	clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000123158	SCV000993568	pathogenic	Familial adenomatous polyposis 2	2018-10-10	criteria provided, single submitter	research
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212711	SCV001134490	pathogenic	not provided	2019-01-18	criteria provided, single submitter	clinical testing	This variant has been reported in homozygous and compound heterozygous individuals with MUTYH-Associated Polyposis (MAP) and colon cancer in the published literature (PMID: 12853198 (2003), 19732775 (2009), 20618354 (2010), 22773231 (2013), 28135145 (2017)). Additionally, functional studies have shown this variant caused exon 10 skipping in the MUTYH transcript, and abolished DNA glycosylase activity in vivo (PMID: 16616356 (2006), 22865608 (2013), 23108399 (2013)). Based on the available information, this variant is classified as pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000212711	SCV001248080	pathogenic	not provided	2023-03-01	criteria provided, single submitter	clinical testing	MUTYH: PVS1, PM3, PM2:Supporting, PS3:Supporting
Department of Pediatrics, Memorial Sloan Kettering Cancer Center	RCV000123158	SCV001478130	pathogenic	Familial adenomatous polyposis 2	2020-12-15	criteria provided, single submitter	research
Department of Molecular Diagnostics, Institute of Oncology Ljubljana	RCV000123158	SCV001499745	pathogenic	Familial adenomatous polyposis 2	2020-04-02	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000212711	SCV001713011	pathogenic	not provided	2020-06-05	criteria provided, single submitter	clinical testing	PVS1, PS3, PM3, PP3, PP5
Genetic Services Laboratory, University of Chicago	RCV000212711	SCV002072049	pathogenic	not provided	2020-05-27	criteria provided, single submitter	clinical testing
AiLife Diagnostics, AiLife Diagnostics	RCV000212711	SCV002502536	pathogenic	not provided	2020-04-03	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000123158	SCV002581012	pathogenic	Familial adenomatous polyposis 2	2022-06-29	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000123158	SCV004198845	pathogenic	Familial adenomatous polyposis 2	2024-03-27	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000129539	SCV004228050	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-12-05	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000123158	SCV004236989	pathogenic	Familial adenomatous polyposis 2	2023-11-20	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000123158	SCV004821947	pathogenic	Familial adenomatous polyposis 2	2024-02-05	criteria provided, single submitter	clinical testing	This variant causes an A to C nucleotide substitution at the +3 position of intron 10 of the MUTYH gene. Functional RNA studies have shown that this variant causes skipping of exon 10, resulting in a frameshift and premature stop codon (p.Gly264Trpfs*7) (PMID: 16616356, 22865608). This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with MUTYH-associated polyposis as homozygous or in trans with another pathogenic variant (PMID: 12853198, 16616356, 18495334, 19732775, 20618354, 22773231, 22865608, 23108399, 27829682), colorectal cancer (PMID: 28135145, 29478780, 35668106), breast cancer (PMID: 30564557, 33606809), or pancreatic ductal adenocarcinoma (PMID: 34506673). This variant is considered a founder mutation in Western Europe (PMID: 22865608). This variant has been identified in 21/282792 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.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000123158	SCV005045792	pathogenic	Familial adenomatous polyposis 2	2019-01-30	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353438	SCV000592702	pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	The MUTYH c.933+3A>C variant was identified in 27 of 1210 proband chromosomes (frequency: 0.022) from individuals or families with polyposis coli or colorectal cancer, and was not identified in 340 control chromosomes from healthy individuals (Kanter-Smoler 2006, Nielsen 2005, Pin 2013, Sampson 2003, Vogt 2009). Most of the probands described in these studies were heterozygous for the variant and had a second MUTYH variant (compound heterozygotes); while one proband from a study by Pin (2013) was homozygous for the variant. The variant was also identified in the “InSiGHT Colon Cancer Database”, HGMD, UMD (33X as a causal variant) and the ClinVar database (with “pathogenic” clinical significance, submitted by Ambry Genetics and Invitae). The c.933+3A>C variant is located in the 5' splice region but does not affect the invariant +1 and +2 positions. However, positions +3 to +6 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. Four out of five in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. Analysis of mRNA in functional studies by Ruggieri (2013) and Pin (2013) have shown that this variant affects splicing, resulting skipping of exon 10 in mRNA transcripts. Protein analysis from these studies demonstrated reduced levels of MUTYH protein, although the amount of protein varied greatly, depending on the second MUTYH mutation in compound heterozygotes. Pin (2013) notes that traces of full-length transcripts and wild-type protein were found in cells homozygous for the variant, suggesting some transcripts may escape from aberrant splicing. The authors of this study found this in agreement with clinical findings in a homozygous proband, who presented with a relatively mild phenotype (attenuated polyposis). In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000626760	SCV000747463	uncertain significance	Colon cancer	2017-01-01	flagged submission	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004542929	SCV004770124	pathogenic	MUTYH-related disorder	2024-07-01	no assertion criteria provided	clinical testing	The MUTYH c.933+3A>C variant is predicted to interfere with splicing. This variant, either in a homozygous state or compound heterozygous state with a second pathogenic mutation, has been reported to be causative for autosomal recessive MUTYH-associated polyposis (Sampson et al. 2003. PubMed ID: 12853198, reported as 891+3A>C; Pin et al. 2013. PubMed ID: 22865608; Ricci et al. 2017. PubMed ID: 27829682). It is reported in 0.014% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/135992/). This variant is interpreted as pathogenic.