Submissions for variant NM_001048174.2(MUTYH):c.254G>A (p.Trp85Ter)

gnomAD frequency: 0.00001  dbSNP: rs888691362

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV000776071	SCV000910773	pathogenic	Hereditary cancer-predisposing syndrome	2020-04-14	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 not been reported in individuals affected with hereditary cancer in the literature. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001206801	SCV000919799	likely pathogenic	Familial adenomatous polyposis 2	2018-07-31	criteria provided, single submitter	clinical testing	Variant summary: MUTYH c.338G>A (p.Trp113X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. c.1147delC, p.Ala385fsX23; c.1227_1228dupGG, p.Glu410fsX43; c.1437_1439delGGA, p.Glu480del). The variant allele was found at a frequency of 1.6e-05 in 121388 control chromosomes (ExAC). To our knowledge, no occurrence of c.338G>A in individuals affected with MUTYH-associated Polyposis and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001206801	SCV001378130	pathogenic	Familial adenomatous polyposis 2	2022-11-26	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 630488). This variant has not been reported in the literature in individuals affected with MUTYH-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Trp113*) 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).
Ambry Genetics	RCV000776071	SCV004057726	pathogenic	Hereditary cancer-predisposing syndrome	2023-06-22	criteria provided, single submitter	clinical testing	The p.W113* pathogenic mutation (also known as c.338G>A), located in coding exon 3 of the MUTYH gene, results from a G to A substitution at nucleotide position 338. This changes the amino acid from a tryptophan to a stop codon within coding exon 3. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). As such, this alteration is interpreted as a disease-causing mutation.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354223	SCV001548783	uncertain significance	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004723164	SCV005338580	pathogenic	MUTYH-related disorder	2024-07-10	no assertion criteria provided	clinical testing	The MUTYH c.338G>A variant is predicted to result in premature protein termination (p.Trp113*). This variant has not been reported in the literature in individuals with MUTYH-associated polyposis. This variant has not been reported in a large population database, indicating this variant is rare. This variant is classified as pathogenic/likely pathogenic by multiple submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/630488/). Nonsense variants in MUTYH are expected to be pathogenic. This variant is interpreted as pathogenic.