Submissions for variant NM_001048174.2(MUTYH):c.1017del (p.Arg340fs)

dbSNP: rs768130289

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV000582105	SCV000690499	pathogenic	Hereditary cancer-predisposing syndrome	2023-02-01	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 expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with MUTYH-associated polyposis and/or colorectal cancer (PMID: 18515411, 19032956, 19732775, 20687945). In one of these affected individuals, this variant has been determined to be compound heterozygous with another pathogenic variant in the same gene (PMID: 19732775), indicating that this variant contributes to MUTYH-associated polyposis in an autosomal recessive manner. This variant has been identified in 1/250124 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.
Ambry Genetics	RCV000582105	SCV001178377	pathogenic	Hereditary cancer-predisposing syndrome	2022-09-15	criteria provided, single submitter	clinical testing	The c.1101delC pathogenic mutation, located in coding exon 12 of the MUTYH gene, results from a deletion of one nucleotide at nucleotide position 1101, causing a translational frameshift with a predicted alternate stop codon (p.R368Gfs*40). This alteration has been previously identified in conjunction with another pathogenic MUTYH mutation in 2 unrelated individuals with colorectal adenomas and/or colorectal cancer (Dallosso AR et al. Gut, 2008 Sep;57:1252-5; Vogt S et al. Gastroenterology, 2009 Dec;137:1976-85.e1-10). 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	RCV001387744	SCV001588453	pathogenic	Familial adenomatous polyposis 2	2023-12-29	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg368Glyfs*40) 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 (no rsID available, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with MUTYH-associated polyposis (PMID: 18515411, 19732775). This variant is also known as c.1092delC. ClinVar contains an entry for this variant (Variation ID: 491999). For these reasons, this variant has been classified as Pathogenic.
All of Us Research Program, National Institutes of Health	RCV001387744	SCV004836309	pathogenic	Familial adenomatous polyposis 2	2023-03-09	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 expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with MUTYH-associated polyposis and/or colorectal cancer (PMID: 18515411, 19032956, 19732775, 20687945). In one of these affected individuals, this variant has been determined to be compound heterozygous with another pathogenic variant in the same gene (PMID: 19732775), indicating that this variant contributes to MUTYH-associated polyposis in an autosomal recessive manner. This variant has been identified in 1/250124 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.