MUTYH-ASSOCIATED POLYPOSIS

MUTYH-Associated Polyposis — an autosomal recessive hereditary colorectal cancer syndrome that mimics attenuated FAP but requires both parents to be carriers, meaning families with 'no family history' of cancer can still produce affected children.

Whole genome sequencing reads the complete MUTYH gene, identifying both alleles simultaneously — the only way to establish the biallelic genotype that defines MAP and distinguishes it from APC-negative attenuated FAP.

MUTYH

About this condition

MUTYH-Associated Polyposis

MUTYH-associated polyposis (MAP) is an autosomal recessive hereditary colorectal cancer predisposition syndrome caused by biallelic pathogenic variants in the MUTYH gene on chromosome 1p34.1, which encodes the MutY DNA glycosylase — a base excision repair enzyme that corrects oxidative DNA damage. Unlike FAP and Lynch syndrome, MAP follows recessive inheritance: both copies of MUTYH must be inactivated for full expression of the syndrome. MAP is characterized by adenomatous polyposis (typically 10-100 polyps, occasionally more), colorectal cancer risk approaching 50-80% by age 70 without surveillance, and a lower but elevated risk of duodenal adenomas and cancer, similar to attenuated FAP.

Two common MUTYH missense variants — c.536A>G (p.Tyr179Cys, formerly Y165C) and c.1187G>A (p.Gly396Asp, formerly G382D) — account for approximately 80% of MAP alleles in individuals of Northern European ancestry. These two variants are so prevalent in European populations that MUTYH heterozygosity (single-allele carrier status) is found in approximately 1-2% of the population — a fact that has practical implications for cancer risk counseling. Biallelic carriers (MAP patients) are most commonly compound heterozygotes of these two common variants. However, in non-European populations, a broader and less characterized spectrum of MUTYH variants contributes to MAP, and fixed two-variant panels have substantially reduced sensitivity.

The autosomal recessive inheritance of MAP has critical clinical implications that differ from dominant hereditary cancer syndromes. A parent with MAP is an obligate MUTYH heterozygote who, if partnered with another carrier (prevalence ~1-2%), has a 25% chance of an affected child. Many MAP patients have no family history of colorectal cancer because parents are unaffected heterozygous carriers. This means MAP should be considered in any patient with 10-100 colorectal adenomas even without a family history. Distinguishing MAP from APC-negative attenuated FAP requires detecting both MUTYH alleles — a task that requires complete MUTYH gene sequencing.

Gene locus: MUTYH (1p34.1)

Two-variant MUTYH panels miss 20% of disease alleles in Europeans and have poor coverage in non-European populations. Identifying biallelic status requires complete gene sequencing — detecting a single allele is never sufficient to diagnose MAP.

A single MUTYH variant on a panel result tells you almost nothing about MAP risk

Standard polyposis panels test for the two common MUTYH p.Tyr179Cys and p.Gly396Asp variants. A report identifying one of these variants describes a heterozygous carrier — a person with no elevated colorectal cancer risk from MAP alone, unless a second MUTYH allele is also present. The clinical action depends entirely on knowing both alleles. If a patient is compound heterozygous for a common MUTYH variant plus a rare variant not tested on a limited panel, they have MAP and require intensive surveillance or prophylactic colectomy. Whole genome sequencing identifies all MUTYH variants across the entire gene simultaneously, enabling definitive biallelic genotyping in a single test.

Non-European MAP patients carry rare MUTYH variants that two-variant panels systematically miss

The p.Tyr179Cys and p.Gly396Asp variants are common in Northern Europeans but are found at much lower frequencies in other populations. MAP in South Asian, East Asian, Middle Eastern, and African ancestry patients is caused by a diverse range of rare MUTYH variants, many of which are population-specific. A patient of South Asian ancestry with attenuated polyposis who tests negative on a two-variant MUTYH panel may have MAP caused by a rare MUTYH allele not represented on the panel. Only complete MUTYH gene sequencing — as provided by whole genome sequencing — has equivalent sensitivity across all ancestry backgrounds.

MUTYH-Associated Polyposis — an autosomal recessive hereditary colorectal cancer syndrome that mimics attenuated FAP but requires both parents to be carriers, meaning families with 'no family history' of cancer can still produce affected children.

MUTYH-Associated Polyposis

Two-variant MUTYH panels miss 20% of disease alleles in Europeans and have poor coverage in non-European populations. Identifying biallelic status requires complete gene sequencing — detecting a single allele is never sufficient to diagnose MAP.

A single MUTYH variant on a panel result tells you almost nothing about MAP risk

Non-European MAP patients carry rare MUTYH variants that two-variant panels systematically miss

Others in Hereditary Cancer

One test. A lifetime of answers.