ClinVar Genomic variation as it relates to human health

This sequence change creates a premature translational stop signal (p.Trp156*) 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 (rs762307622, gnomAD 0.09%). This premature translational stop signal has been observed in individual(s) with colorectal cancer (PMID: 25151137, 28127763). This variant is also known as c.425G>A (p.W142X). ClinVar contains an entry for this variant (Variation ID: 230971). Studies have shown that this premature translational stop signal is associated with inconclusive levels of altered splicing (Invitae). For these reasons, this variant has been classified as Pathogenic.

The p.W156* pathogenic mutation (also known as c.467G>A), located in coding exon 6 of the MUTYH gene, results from a G to A substitution at nucleotide position 467. This changes the amino acid from a tryptophan to a stop codon within coding exon 6. This alteration was reported as a germline mutation in an individual with advanced stage colorectal cancer whose tumor showed loss of heterozygosity for MUTYH (Pilati C et al. J. Pathol. 2017 May;242:10-15). 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.

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; Observed in individuals with colorectal cancer (Guan et al., 2015; Pilati et al., 2017; Cohen et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25151137, 28127763, 31203172, 30151276, 29625052, 33230973, 30787465, 34308366, 33830941, 34259353, 36988593, 28873162, 36095024, 36243179, 35273153, 32980694, 35070997, 35422474, 36655350, 36315097)

This variant changes 1 nucleotide in exon 6 of the MUTYH gene, creating a premature translation stop signal. This variant is also known as p.W142X (c.425G>A) in the literature based on an alternate trasncript NM_001048171. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with colorectal cancer (PMID: 25151137, 28127763, 30151276). In two of these individuals, tumors showed loss of hetereozygosity for the MUTYH gene (PMID: 28127763, 30151276). This variant has been identified in 16/281728 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.

This variant changes 1 nucleotide in exon 6 of the MUTYH gene, creating a premature translation stop signal. This variant is also known as p.W142X (c.425G>A) in the literature based on an alternate trasncript NM_001048171. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with colorectal cancer (PMID: 25151137, 28127763, 30151276). In two of these individuals, tumors showed loss of hetereozygosity for the MUTYH gene (PMID: 28127763, 30151276). This variant has been identified in 16/281728 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.

The MUTYH p.Trp156X variant was not identified in the literature nor was it identified in the NHLBI Exome Sequencing Project (Exome Variant Server), GeneInsight COGR, COSMIC, MutDB, InSiGHT Colon Cancer, Zhejiang Colon Cancer, the ClinVar, Clinvitae and UMD Colon Cancer Genes databases. The variant is listed in the dbSNP database (ID#: rs762307622) but no frequency information was provided, thus the prevalence of this variant in the general population could not be determined. The variant was identified in Exome Aggregation Consortium (ExAC) database (January 13, 2015) in 6 of 121000 alleles (frequency: 0.00005) or 5 of 8628 East Asian and 1 other population alleles and was not found in a population of South Asians, European (Non-Finnish), African, Latino, European (Finnish) and other individuals. The p.Trp156X variant leads to a premature stop codon at position 156, 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.