Submissions for variant NM_001048174.2(MUTYH):c.1272del (p.Tyr425fs)

dbSNP: rs1553125243

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000550116	SCV000639276	pathogenic	Familial adenomatous polyposis 2	2024-01-03	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr453Ilefs*14) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with colorectal adenoma (PMID: 17219385). This variant is also known as c.1314delA (p.Val452X). ClinVar contains an entry for this variant (Variation ID: 464690). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000570640	SCV000666456	pathogenic	Hereditary cancer-predisposing syndrome	2021-06-19	criteria provided, single submitter	clinical testing	The c.1356delA pathogenic mutation, located in coding exon 14 of the MUTYH gene, results from a deletion of one nucleotide at nucleotide position 1356, causing a translational frameshift with a predicted alternate stop codon (p.Y453Ifs*14). This truncating mutation was detected in conjunction with a second pathogenic MUTYH mutation in an individual with MUTYH-associated polyposis (MAP) (Croitoru ME et al J. Surg. Oncol. 2007 May; 95(6):499-506). This mutation has also been detected in a patient with advanced cancer (Mandelker D et al. JAMA. 2017 Sep 5;318(9):825-835). 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.
Color Diagnostics, LLC DBA Color Health	RCV000570640	SCV000904314	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 14 of the MUTYH gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has not been identified 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.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV001800753	SCV002011064	pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001800753	SCV002046871	pathogenic	not provided	2021-04-08	criteria provided, single submitter	clinical testing	This frameshift variant causes the premature termination of MUTYH protein synthesis. It has been reported along with another pathogenic MUTYH variant in an individual with familial colorectal cancer in the published literature (PMID: 17219385 (2007)). Therefore, the variant is classified as pathogenic.
Baylor Genetics	RCV000550116	SCV004199403	pathogenic	Familial adenomatous polyposis 2	2023-02-22	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000550116	SCV004832243	pathogenic	Familial adenomatous polyposis 2	2023-12-07	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 14 of the MUTYH gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has not been identified 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	RCV000550116	SCV004848034	pathogenic	Familial adenomatous polyposis 2	2021-03-26	criteria provided, single submitter	clinical testing	The p.Tyr453IlefsX14 variant in MUTYH has been reported in the compound heterozygous state in 1 individual with polyposis and colorectal cancer (Croitoru 2007 PMID: 17219385). It has also been identified in heterozygous state in individuals with endometrial and pancreatic cancers (Ring 2016 PMID: 27443514, Lowery 2018 PMID: 29506128). It was absent from large population studies and has been reported as Pathogenic by multiple laboratories in ClinVar (Variation ID 464690). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 453 and leads to a premature termination codon 14 amino acids downstream. This alteration is then 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, PM3_Supporting, PM2_Supporting.