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Condition report · Cancer

Lynch Syndrome

Whole genome sequencing identifies the specific mismatch repair gene variant, giving you and your family the certainty to act on what you inherit before cancer develops.

A condition report looks for rare variants known to cause the conditions it covers.

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About this condition

An inherited cancer predisposition caused by faults in DNA mismatch-repair genes (MLH1, MSH2, MSH6, PMS2, EPCAM). It raises the lifetime risk of colorectal and endometrial cancer, as well as ovarian, stomach, urinary tract and other cancers.

Lynch Syndrome is caused by inherited variants in genes that encode proteins of the DNA mismatch repair (MMR) system: MLH1, MSH2, MSH6, and PMS2. These proteins correct errors in DNA replication; when they fail, mutations accumulate unchecked, accelerating tumor formation. The result is a syndrome characterized by lifetime colorectal cancer risk of 40-80%, with endometrial cancer in women being the second most common manifestation.

Approximately 1 in 279 people carry a Lynch Syndrome variant, making it the most common hereditary colorectal cancer syndrome. The two most commonly implicated genes, MLH1 and MSH2, confer the highest cancer risks and the earliest age of onset. MSH6 and PMS2 variants are associated with later onset and lower overall lifetime cancer risk, yet still warrant enhanced surveillance. The syndrome also accounts for 2-5% of all colorectal cancers in the population.

Identifying the specific gene involved has immediate clinical implications. A Lynch variant follows autosomal dominant inheritance, meaning each child of a carrier has a 50% chance of inheritance. Colonoscopy screening every 1-2 years starting at age 20-25 reduces colorectal cancer mortality by approximately 65%. Women qualify for gynecological risk assessment and may elect risk-reducing surgery. For tumors that develop with MSI-high status, immunotherapy (pembrolizumab) produces dramatic responses. One person's genetic finding opens the door to preventive action across the entire family.

Lynch Syndrome is genetically stratifiable: MLH1 and MSH2 carriers have the highest cancer risks with earlier age of onset; MSH6 carriers have later onset with lower lifetime risk; PMS2 carriers have the mildest phenotype. These gene-specific risk profiles guide the intensity of surveillance.

The 2 conditions we analyse

Lynch Syndrome

Autosomal dominant

Hereditary nonpolyposis colorectal cancer syndrome caused by germline mismatch-repair defects, with early-onset colorectal, endometrial and other cancers.

What a diagnosis changes

Enhanced colonoscopy surveillance, aspirin chemoprevention, immune checkpoint inhibitors for MSI-high tumors, cascade testing, risk-reducing gynecological surgery

Genes analysed

Also known as

familial non-polyposis colon cancer (hMSH2, hMLH1, hPMS1, hPMS2); Hereditary colorectal endometrial cancer syndrome; hereditary defective mismatch repair syndrome; Hereditary non-polyposis colon cancer (hMSH2, hMLH1, hPMS1, hPMS2); Hereditary nonpolyposis colon cancer (hMSH2, hMLH1, hPMS1, hPMS2)

Includes 5 related subtypes ↓
  • Lynch syndrome 1
  • Lynch syndrome 2
  • Lynch syndrome 4
  • Lynch syndrome 5
  • Lynch syndrome 8
MONDO:0005835Orphanet 144MedGen 1633554

Muir-Torre syndrome

Autosomal dominant

A form of Lynch syndrome, usually caused by MSH2 or MLH1 variants, in which sebaceous skin tumours or keratoacanthomas occur alongside internal cancers.

What a diagnosis changes

Lynch syndrome surveillance plus regular skin examination.

Genes analysed

Also known as

cutaneous sebaceous neoplasms and keratoacanthomas multiple with gastrointestinal and other carcinomas; MRTES; multiple keratoacanthoma, Muir-Torre type

MONDO:0008018OMIM 158320Orphanet 587MedGen 231157

Example variants this report looks at

For each condition, a few of the variants ClinVar classifies under it, those with most review stars. Each page describes ClinVar's public record of the variant, never a result.

VariantGeneClinVar classificationReview status
A21EMLH1Pathogenic3 stars out of 4 reviewed by expert panel
A21Rfs*15MLH1Pathogenic3 stars out of 4 reviewed by expert panel
A21VMLH1Pathogenic3 stars out of 4 reviewed by expert panel

1596 more variants under Lynch Syndrome have a page. Every variant, by gene:

Why whole genome sequencing

Standard Lynch panels focus on MLH1, MSH2, MSH6, and PMS2 alone. Up to 20% of Lynch families have EPCAM deletions that standard sequencing misses entirely.

Structural variants slip through standard sequencing

Lynch Syndrome can be caused by large deletions in EPCAM (located upstream of MSH2) that silence MSH2 expression through promoter methylation. These rearrangements are not detectable by short-read sequencing panels; they require specialized deletion analysis that most standard tests do not perform. Whole genome sequencing reads the full DNA sequence at sufficient depth to identify structural variants, capturing the full variant landscape in Lynch families.

One result changes cancer prevention for your whole family

Lynch Syndrome variants follow predictable inheritance patterns, enabling cascade testing across families at risk. When a pathogenic MLH1, MSH2, MSH6, or PMS2 variant is identified, first-degree relatives can be offered targeted genetic testing, converting one person's diagnosis into actionable preventive opportunities for siblings, parents, and children. Relatives identified through cascade testing can begin surveillance at age 20-25, potentially preventing cancers before they develop.

Other cancer conditions

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