MLH1 Gene: Lynch Syndrome Cancer Risk by Age and Sex

01 / 10

What is the MLH1 gene?

The MLH1 gene, on chromosome 3 at 3p22.2, makes a protein that helps repair copying mistakes in DNA. MLH1 pairs with PMS2 to form MutL alpha, part of the DNA mismatch repair system. A harmful variant in one copy of MLH1 causes Lynch syndrome. ^[1,8]

Everyone normally has two MLH1 copies. NCBI lists the aliases FCC2, COCA2, HNPCC2, LYNCH2, hMLH1 and MMRCS1. GeneReviews estimates MLH1 variants account for 15–40% of Lynch syndrome; MedlinePlus says up to 40%. About 1 in 3,000 people in the United States carries an MLH1 variant, while Lynch syndrome overall affects about 1 in 280–600. ^[1,7,8,11]

“MLH1” also appears in yeast research and pathology stain reports. This page concerns the inherited human gene. Read the Lynch syndrome overview for the condition-level picture.

02 / 10

How do MLH1 variants cause Lynch syndrome?

MLH1 variants cause Lynch syndrome by switching off one working copy of a DNA repair gene. Cells retain one normal copy until a second, later hit disables it. Copying errors then accumulate in that tissue, which is why Lynch tumours show microsatellite instability. Hundreds of different MLH1 variants have been found. ^[1,7]

Loss-of-function changes include missense, truncating and splice variants and large deletions. Classification follows ClinGen MLH1 Variant Curation Expert Panel specifications and ACMG/AMP principles. ClinGen classified the MLH1–Lynch syndrome relationship as Definitive on June 20, 2022. ^[1,6,9,14]

03 / 10

MLH1 cancer risk by cancer type, age and sex

People with a pathogenic MLH1 variant have one of the highest colorectal cancer risks of any Lynch gene. NCCN Version 1.2026 gives 46–61% lifetime risk. In the Prospective Lynch Syndrome Database, colon cancer risk by age 65 was 36% in women and 48% in men. ^[1,2,11]

Cumulative risk through age 65

General population and MLH1 carrier cumulative cancer risk through age 65, female and male.
Cancer	General population F / M	MLH1 carriers F / M
Colon	0.45% / 0.6%	36% / 48%
Rectum	0.3% / 0.5%	5% / 6%
Endometrium	0.6%	32%
Ovary	0.5%	8%
Ureter, kidney	0.2% / 0.35%	2% / 2.5%
Prostate	1% (M)	5% (M)
Small bowel	Unknown	2.5% / 4%
Bladder	0.1% / 0.35%	1% / 3%
Gastric	0.3% / 0.6%	2% / 3%
Brain	0.2% / 0.25%	1% / 0%
Bile duct	Unknown	1.5% / 3%
Pancreas	0.2% / 0.25%	2% / 1%

Source: GeneReviews Table 3, updated September 17, 2026, using PLSD data through October 2022 from 8,500 carriers and 71,713 follow-up years. General-population comparison is IARC GLOBOCAN risk through age 64. ^[1,4,12]

NCCN lifetime ranges

Cancer	MLH1 lifetime risk	General population	Average age: MLH1 / general
Colorectal	46–61%	4%	44 / 68–72
Endometrial	34–54%	3.1%	49 / 60
Ovarian	4–20%	1.1%	46 / 63
Gastric	5–7%	—	—
Bladder	Up to 7%	—	—
Kidney / ureter	Up to 5%	—	—
Small bowel	0.4–11%	—	—
Brain	0.7–1.7%	—	—
Biliary	1.9–3.7%	—	—
Pancreatic	6.2%	—	—

NCCN Version 1.2026 as reproduced by FORCE on September 24, 2026; ovarian and pancreatic rows also draw on NCCN Version 1.2027. ^[2,3,11]

Why the numbers differ: NCCN ranges are lifetime estimates pooled from several studies. PLSD estimates are prospective through age 65 in carriers already receiving colonoscopy surveillance. They are therefore lower for colon cancer and cannot be compared line by line. ^[1,2,4]

PLSD reported median age at any-organ cancer of 48.4 years in men and 51.3 in women; median colorectal onset was 47.4 in men and 54.6 in women. Not everyone with an MLH1 variant develops cancer. The four mismatch-repair genes have different penetrance rather than forming one uniform syndrome. ^[5,13]

04 / 10

How MLH1 differs from the other Lynch genes

MLH1 and MSH2 carry the highest colorectal cancer risk among the four Lynch genes, while MSH6 and PMS2 carry lower and later-onset risk. By age 65, PLSD estimates colon cancer at 36% in women and 48% in men for MLH1, compared with 30% and 41.5% for MSH2. ^[1]

Cancer risk through age 65 by Lynch syndrome gene.
Cancer through 65	MLH1	MSH2	MSH6	PMS2
Colon F / M	36% / 48%	30% / 41.5%	10% / 13%	3% / 9.5%
Endometrium	32%	38%	32%	13%
Ovary	8%	11%	3%	2.5%

GeneReviews Table 3 uses PLSD data. The PMS2 estimates rest on only 549 carriers—6.5% of the 8,500-person cohort—so their uncertainty is wider. ^[1]

Compare the MSH2 gene, MSH6 gene and PMS2 gene guides.

05 / 10

What does “MLH1 positive” mean?

On a genetic test report, “MLH1 positive” means a pathogenic or likely pathogenic variant was found in MLH1, which establishes Lynch syndrome. On a tumour pathology report, “MLH1 positive” usually means the MLH1 protein is present on staining—the normal result. A variant of uncertain significance neither confirms nor rules out Lynch syndrome. ^[1,9]

Report context	What the result means	What happens next
Germline “positive”	A pathogenic or likely pathogenic MLH1 variant was identified	Clinical confirmation, genetic counselling, gene-specific surveillance and family testing
Tumour IHC “positive”	MLH1 protein is retained or present—the normal staining result	Interpret with PMS2 and the other mismatch-repair proteins
Tumour MLH1 loss	Abnormal absent staining; often caused by sporadic MLH1 promoter methylation	Methylation and/or BRAF assessment may precede germline testing
Variant of uncertain significance	Evidence cannot show whether the variant is harmful	Do not use it alone to diagnose Lynch syndrome or make irreversible decisions

Pathogenic and likely pathogenic variants are treated alike clinically under ACMG/AMP classification. Tumour staining and inherited DNA testing answer different questions. Loss of MLH1 in a tumour is often sporadic promoter methylation rather than an inherited variant. Read about tumour MSI and IHC testing. ^[1,9,10]

A positive germline result begins counselling, confirmation where appropriate and risk management. It is not a diagnosis of cancer.

06 / 10

How MLH1 variants run in families

An MLH1 variant is inherited in an autosomal dominant pattern, so each child of a carrier has a 50% chance of inheriting it, and it does not skip generations. Relatives can be offered testing for the one known family variant. A child who inherits an MLH1 variant from both parents has a separate, far more severe condition. ^[1,11]

50%

Each pregnancy is an independent event, and the variant may come from either parent. Cascade testing starts with the exact familial variant. Routine predictive testing of children is not recommended for adult-onset Lynch syndrome.

Biallelic variants in MLH1, MSH2, MSH6 or PMS2 can cause constitutional mismatch repair deficiency (CMMRD), but only when both parents carry a relevant variant. Most first tumours occur before age 18; about half of affected children develop cancer by age 10. ClinGen classifies MLH1–CMMRD as Definitive, while evidence for paediatric actionability of monoallelic Lynch syndrome is insufficient. ^[1,6,7]

07 / 10

Screening and prevention for MLH1 carriers

For people with an MLH1 variant, NCCN Version 1.2026 advises colonoscopy every 1–2 years starting at age 20–25, or 2–5 years before the youngest colorectal cancer in the family. GeneReviews lists the same schedule for MLH1. Individual plans are set with a genetic counsellor or clinician. ^[1,2,11]

Area	When to discuss or start	Interval / note
Colonoscopy	Age 20–25; or 2–5 years before the youngest family diagnosis	Every 1–2 years
Endometrial biopsy	Consider from age 30–35	Every 1–2 years; evidence of mortality benefit is limited
Transvaginal ultrasound	After menopause	Optional; not a reliable stand-alone screen
Hysterectomy with salpingectomy	Discuss from age 40	Individual decision after childbearing and review of benefits and harms
Ovarian cancer	Symptom awareness	No routine CA-125 or ultrasound screening
Upper endoscopy and H. pylori	Age 30–40	Every 2–4 years; include H. pylori testing
Pancreatic MRI/MRCP or EUS	Age 50 only with relevant family history	Annually in an experienced centre
Skin examination	Any age after individual review	Every 1–2 years
Aspirin	Discuss with a clinician	Dose, duration and bleeding risk require individual review

eviQ’s April 2024 guidance uses age 25 for colonoscopy, but its review date has passed; Myriad gives 20–25. Current GeneReviews and NCCN-based guidance is shown here. Read the detailed colonoscopy schedule and aspirin guide and the guide to endometrial and ovarian cancer in Lynch syndrome. ^[1,2,11,16]

08 / 10

How MLH1 variants are found, and what testing can miss

MLH1 variants are found by DNA sequencing plus a separate deletion and duplication analysis, usually within a multigene panel. Sequencing detects about 80–90% of MLH1 pathogenic variants and deletion/duplication analysis the other 10–20%. Constitutional MLH1 promoter methylation, a rare cause of Lynch syndrome, cannot be seen by either method. ^[1,10]

Sequence analysis

80–90%

Share of MLH1 pathogenic variants detected by sequencing in GeneReviews Table 1.

Deletion / duplication

10–20%

Requires a separate copy-number method rather than sequence analysis alone.

Promoter methylation

Not detected

Constitutional MLH1 methylation needs a dedicated methylation assay.

Promoter methylation changes gene activity without changing the DNA letter sequence or gene copy number. Standard sequencing and deletion/duplication analysis therefore miss it. Variant classification follows ClinGen MLH1 VCEP specifications. Any research or consumer finding needs clinical confirmation and counselling. ^[1,10,14]

Tumour MSI and IHC are performed on cancer tissue and are not germline DNA tests. Read how Lynch syndrome genetic testing works and the separate guide to tumour MSI and IHC testing.

09 / 10

MLH1 questions people ask

Q1What does MLH1 positive mean?

On a germline report, it means a pathogenic or likely pathogenic MLH1 variant was found and establishes Lynch syndrome. On tumour IHC, “positive” usually means MLH1 protein is present. A positive genetic result is not a cancer diagnosis. ^[1,9]

Q2What is the cancer risk for people with an MLH1 mutation?

NCCN Version 1.2026 gives 46–61% lifetime colorectal cancer risk and 34–54% endometrial cancer risk. GeneReviews reports colon cancer risk through age 65 of 36% in women and 48% in men. ^[1,2,11]

Q3Does everyone have the MLH1 gene?

Yes. Everyone normally has two copies of MLH1. One pathogenic copy can cause Lynch syndrome; cancer usually develops only after a cell later loses the remaining working copy. ^[1,8]

Q4What is the most common mutation in Lynch syndrome?

There is no single most common mutation. Hundreds of MLH1 variants are known. GeneReviews estimates MLH1 accounts for 15–40% of Lynch syndrome and MSH2 for 20–40%. ^[1,7]

Q5Does MLH1 raise breast cancer risk?

ClinGen classified the claimed MLH1–hereditary breast carcinoma relationship as Refuted on December 21, 2023. General breast screening remains appropriate unless personal or family history supports a different plan. ^[6]

Q6Does everyone with an MLH1 variant get cancer?

No. MLH1 has incomplete penetrance, so risk is high but below 100%. Risk changes with age, sex, cancer type, family history and surveillance. ^[1,13]

10 / 10

Why whole-genome sequencing, and where it falls short

Whole-genome sequencing reads broadly across the genome, whereas a Lynch panel reads a fixed list of genes with methods chosen for a clinical question. HLI describes a $599 genome service with a cancer risk assessment covering BRCA1 and BRCA2 among other genes; its MLH1 and other Lynch-gene coverage is not published. A genome finding is a starting point, not a diagnosis.

Confirmatory clinical testing and a genetic counsellor should follow a potentially important finding. A sequence cannot show an existing cancer or provide tumour MSI/IHC results.

Route	What it can add	Important limit
Clinical Lynch / multigene panel	Clinician-ordered after counselling; includes gene-specific deletion/duplication analysis and ClinGen-based classification	A fixed gene list, but the better route for a known family variant or strong personal or family history; insurance may cover testing when criteria are met
Tumour-first pathway	MSI and IHC on colorectal or endometrial tumour tissue can identify mismatch-repair loss before germline testing	Not inherited-DNA testing; WGS does not perform tumour testing
23andMe	Its clinician-ordered Total Health exome report lists Lynch syndrome for MLH1, MSH2, MSH6 and PMS2	Standard Health Predisposition reports do not include Lynch genes; the added report is an exome, not a genome, and EPCAM is not listed
Whole-genome sequencing	Broad sequence data can support assessment beyond a fixed panel	Does not detect MLH1 promoter methylation, guarantee every position or variant, find cancer today, replace screening, or provide tumour MSI/IHC

HLI states approximately 30× average coverage, which does not guarantee coverage at every position. Its MLH1 copy-number performance, confirmation workflow and counselling inclusion are unpublished. A clinical panel remains the stronger first choice when Lynch syndrome is already suspected. The 23andMe comparison reflects its reports list read October 5, 2026. ^[1,10,15]

See what the $599 genome service includes, or read about BRCA1 and BRCA2 risk in the broader cancer-risk context.

References and review notes

Sources and versions were reviewed October 5, 2026. GeneReviews and NCCN should be checked every six months and whenever revised; next planned review is January 5, 2027. HLI assay coverage, copy-number performance, confirmation workflow and counselling inclusion remain unverified.