Submissions for variant NM_001048174.2(MUTYH):c.225G>A (p.Trp75Ter)

dbSNP: rs748170941

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164326	SCV000214957	pathogenic	Hereditary cancer-predisposing syndrome	2021-08-10	criteria provided, single submitter	clinical testing	The p.W103* pathogenic mutation (also known as c.309G>A), located in coding exon 3 of the MUTYH gene, results from a G to A substitution at nucleotide position 309. This changes the amino acid from a tryptophan to a stop codon within coding exon 3. This alteration was reported in conjunction with an MUTYH founder mutation in an Australian woman with early-onset adenomatous polyposis (Kairupan CF et al. Int. J. Cancer, 2005 Aug;116:73-7). This alteration was also identified in an individual diagnosed with pancreatic cancer (Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the 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	RCV000196257	SCV000253865	pathogenic	Familial adenomatous polyposis 2	2024-01-13	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp103*) 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 (rs748170941, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with adenomatous polyposis (PMID: 15761860). This variant is also known as G267A (W89X). ClinVar contains an entry for this variant (Variation ID: 184976). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000523882	SCV000617565	pathogenic	not provided	2024-01-30	criteria provided, single submitter	clinical testing	Nonsense 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: 25525159, 28152038, 34761457, 32885271, 15761860)
Counsyl	RCV000196257	SCV000678197	likely pathogenic	Familial adenomatous polyposis 2	2017-03-15	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000164326	SCV000690556	pathogenic	Hereditary cancer-predisposing syndrome	2023-05-04	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 3 of the MUTYH gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in an individual affected with colorectal polyposis in compound heterozygous state with a known pathogenic variant p.Gly382Asp (PMID: 15761860). This variant has been identified in 1/251488 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000523882	SCV000888311	pathogenic	not provided	2017-11-24	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000196257	SCV000915418	pathogenic	Familial adenomatous polyposis 2	2024-07-22	criteria provided, single submitter	clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000196257	SCV000993569	pathogenic	Familial adenomatous polyposis 2	2018-12-10	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000196257	SCV001448571	pathogenic	Familial adenomatous polyposis 2	2023-04-27	criteria provided, single submitter	clinical testing	Variant summary: MUTYH c.309G>A (p.Trp103X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 4e-06 in 251488 control chromosomes. c.309G>A has been reported in the literature in at least one individual affected with MUTYH-Associated Polyposis (Kairupan_2005). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 15761860). Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified as Pathogenic (n=6), Likely Pathogenic (n=2) and VUS (n=1. Based on the evidence outlined above, the variant was classified as pathogenic.
Revvity Omics, Revvity	RCV000196257	SCV002017628	pathogenic	Familial adenomatous polyposis 2	2019-05-24	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000196257	SCV004198877	pathogenic	Familial adenomatous polyposis 2	2024-01-24	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000196257	SCV004837931	pathogenic	Familial adenomatous polyposis 2	2023-10-30	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 3 of the MUTYH gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, this variant has been reported in individuals affected with colorectal polyposis (PMID: 15761860). This variant has been identified in 1/251488 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	RCV000196257	SCV004847860	pathogenic	Familial adenomatous polyposis 2	2020-04-14	criteria provided, single submitter	clinical testing	The p.Trp103X variant in MUTYH has been reported in the compound heterozygous state in 1 individual with MUTYH-associated polyposis (Aretz 2006, Vogt 2009, Sutcliffe 2019). It has been identified in 0.001% (1/113764) of chromosomes in Europeans by gnomAD (http://gnomad.broadinstitute.org).This variant has also been reported in ClinVar (Variation ID 184976). This nonsense variant leads to a premature termination codon at position 103, which is predicted to lead to a truncated or absent protein. Loss of function of the MUTYH gene is an established disease mechanism in autosomal recessive MUTYH-associated polyposis. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive MUTYH-associated polyposis. ACMG/AMP criteria applied: PVS1, PM2, PM3.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000523882	SCV000592677	pathogenic	not provided		no assertion criteria provided	clinical testing	The MUTYH p.Trp103* variant was identified in 1 of 364 proband chromosomes (frequency: 0.003) from individuals or families with adenomatous polyposis (Kairupan 2005). The individual identified in this study was a compound heterozygote with a second pathogenic MUTYH mutation, p.Gly382Asp.The variant was also identified in dbSNP (ID: rs748170941) as "With Pathogenic allele ", ClinVar (classified as pathogenic by Invitae, Ambry Genetics and three other submitters; as likely pathogenic by Counsyl), and in the COGR database. The variant was not identified in Cosmic, or UMD-LSDB. The variant was identified in control databases in 1 of 246268 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European in 1 of 111716 chromosomes (freq: 0.000009), but not in other populations. The p.Trp103* variant leads to a premature stop codon at position 103, which is predicted to lead to 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 summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.