# Lynch Syndrome

Use universal colorectal and endometrial tumor mismatch-repair testing to identify candidates for germline evaluation, distinguish sporadic MLH1-deficient tumors, and implement gene-informed colonoscopic surveillance, cascade testing, and gynecologic risk reduction.

**Clinical question:** How should physicians diagnose Lynch syndrome and direct cancer surveillance and preventive management after a pathogenic variant is identified?

Updated: 2026-09-15T17:19:32.721231+00:00

## What matters in practice
- Evaluate newly diagnosed colorectal cancer with tumor mismatch-repair immunohistochemistry or microsatellite-instability testing regardless of age or family-history criteria; clinical criteria alone miss many carriers. [16][23]
- For colorectal tumors with MLH1/PMS2 loss, use BRAF V600E and/or MLH1 promoter methylation testing to identify the common sporadic MLH1-deficient pathway before germline testing; BRAF testing is not appropriate for noncolorectal tumors. [20][22][24]
- Absent MSH2/MSH6, isolated MSH6, or isolated PMS2 expression on tumor immunohistochemistry should prompt germline mismatch-repair gene evaluation after genetics counseling. [20][23]
- After a germline Lynch syndrome diagnosis, colonoscopy every 1 to 2 years is the central prevention strategy; begin 2 to 5 years before the earliest colorectal cancer in the family. [17]
- Counsel patients with a uterus and ovaries about risk-reducing hysterectomy with bilateral salpingo-oophorectomy after childbearing, because surgery is the definitive preventive option for endometrial and ovarian cancer. [5][8][9]

## Identify Lynch syndrome through tumor-first testing

Do not rely on pedigree criteria as the sole gatekeeper for evaluation.

Order mismatch-repair (MMR) protein immunohistochemistry (IHC) and/or microsatellite-instability (MSI) testing for newly diagnosed colorectal cancer. Universal tumor screening detects cases that age- and family-history criteria miss; Amsterdam and revised Bethesda criteria have important sensitivity and specificity limitations. [16][23]

Apply the same tumor-testing framework to endometrial carcinoma when feasible. Tumor-testing strategies are established for colorectal and endometrial cancers, whereas evidence for routine application to other Lynch-spectrum tumors is more limited. [20]

Trigger genetics referral and germline testing when tumor findings suggest inherited MMR deficiency, when a patient has a personal or family pattern of Lynch-spectrum cancers, or when the clinical probability remains concerning despite nondiagnostic tumor testing. Lynch-associated tumors include colorectal, endometrial, ovarian, gastric, small-bowel, pancreatic, biliary tract, upper urinary tract, bladder, prostate, brain, and sebaceous skin tumors. [16][17][21]
- Obtain a three-generation pedigree that records cancer site and age at diagnosis; prioritize colorectal, endometrial, ovarian, gastric, small-bowel, upper urinary tract, pancreatic, biliary, brain, prostate, and sebaceous neoplasms. [16][17][21]
- Test an affected relative's tumor before testing unaffected relatives whenever available, because tumor results direct the appropriate germline analysis. [20][23]
- Do not use a normal family history to exclude Lynch syndrome from a patient with a newly diagnosed colorectal cancer. Universal screening is designed to identify carriers outside classic clinical criteria. [16][23]

*Tumor-first triage for Lynch syndrome evaluation in colorectal and endometrial cancer. [20][23][24]*

| Tumor result | Most relevant interpretation | Next action |
| --- | --- | --- |
| All four MMR proteins retained and microsatellite stable | Usually sporadic cancer; a germline MMR pathogenic variant remains possible in an MSI-high tumor with retained IHC. [20] | Reassess personal and family history; pursue genetics evaluation if clinical suspicion remains high. [20][23] |
| MLH1 and PMS2 loss in colorectal cancer | Frequently reflects acquired MLH1 promoter methylation rather than Lynch syndrome. [22][24] | Order MLH1 promoter methylation and/or BRAF V600E testing. Germline evaluation is indicated when the sporadic pathway is not demonstrated. [20][24] |
| MLH1 and PMS2 loss in endometrial cancer | MLH1 promoter methylation can distinguish an acquired defect; BRAF testing is not appropriate outside colorectal cancer. [20] | Order MLH1 promoter methylation testing; refer for germline evaluation if methylation is absent or clinical suspicion persists. [20] |
| MSH2 and MSH6 loss | Pattern is compatible with an inherited MSH2-pathway defect, including EPCAM-associated MSH2 silencing. [20] | Refer for germline MMR evaluation with genetics counseling. [20][23] |
| Isolated MSH6 loss | Pattern is compatible with an MSH6-pathway defect. [20] | Refer for germline MMR evaluation with genetics counseling. [20][23] |
| Isolated PMS2 loss | Pattern is compatible with a PMS2-pathway defect. [20] | Refer for germline MMR evaluation with genetics counseling. [20][23] |

## Separate sporadic MLH1 deficiency from inherited MMR deficiency

The MLH1/PMS2-loss branch requires an additional somatic workup before assigning inherited risk.

MMR IHC identifies loss of the MLH1, MSH2, MSH6, or PMS2 protein products; MSI testing identifies the genomic instability caused by MMR dysfunction. Either abnormality establishes MMR deficiency but does not by itself establish Lynch syndrome, because sporadic colorectal cancers can be MSI-high or MMR-deficient through acquired MLH1 methylation. [18][22]

In colorectal cancer with MLH1/PMS2 loss, a positive BRAF V600E result supports a sporadic MLH1-deficient tumor. MLH1 promoter methylation similarly supports acquired MLH1 silencing; when BRAF is negative and MLH1 methylation is absent, proceed to germline testing for Lynch syndrome. [20][22][24]

Do not extrapolate BRAF triage to endometrial cancer or other tumors. For noncolorectal tumors with MLH1 loss, MLH1 promoter methylation is the relevant tumor assay in the supplied testing framework. [20]

Interpret MSI and IHC as complementary rather than interchangeable when suspicion is high. MSI sensitivity is reported as lower for MSH6 and PMS2 carriers than for MLH1 and MSH2 carriers, making IHC particularly useful in the MSH6/PMS2 branch. [18]
- If IHC shows isolated PMS2 loss, do not dismiss Lynch syndrome because PMS2-associated cancer risks are lower than those associated with some other MMR genes. [1][16]
- If tumor testing is abnormal but germline testing is negative, retain oncology-directed interpretation of the tumor's MMR status and reassess whether additional tumor or hereditary cancer evaluation is warranted based on the clinical context. [20][21]
- Document the exact germline pathogenic variant when identified; cancer risks and management discussions vary by MLH1, MSH2, MSH6, PMS2, and EPCAM pathway. [1][9][16]

*Key limitations of clinical and tumor screening approaches. [16][18][19][23]*

| Approach | Strength | Limitation affecting action |
| --- | --- | --- |
| Amsterdam II criteria | High specificity in one colorectal cancer cohort. [19] | Limited sensitivity; criteria-based selection misses carriers. [16][19][23] |
| Revised Bethesda criteria | High sensitivity in one colorectal cancer cohort. [19] | Low specificity in that cohort and does not replace universal tumor testing. [19][23] |
| MSI testing | Detects the MMR-deficient phenotype. [18][22] | Sensitivity is lower for MSH6 and PMS2 than for MLH1 and MSH2 carriers. [18] |
| MMR IHC | Directs gene-specific germline testing according to loss pattern. [20] | Abnormal staining also occurs in sporadic MLH1-methylated cancers. [18][22] |

## Confirm the inherited diagnosis and extend testing to relatives

A pathogenic germline variant changes surveillance for the patient and targeted testing for relatives.

Confirm Lynch syndrome by identifying a germline pathogenic variant in MLH1, MSH2, MSH6, PMS2, or EPCAM-associated MSH2 pathway disease after pretest counseling. Lynch syndrome is autosomal dominant; once the familial pathogenic variant is known, offer targeted testing to biologic relatives rather than broad, untargeted testing. [1][16]

Use the family's identified variant to distinguish relatives who need Lynch-specific prevention from those who do not carry that familial pathogenic variant. Cascade testing is clinically consequential because intensive colonoscopic surveillance and gynecologic risk-reduction decisions should be concentrated in confirmed carriers. [17][20]

Treat gene identity as a risk modifier rather than a reason to abandon surveillance. MSH6 and PMS2 variants generally confer lower risks of colorectal and other Lynch-associated malignancies than MLH1 or MSH2 variants, and PMS2 variants are associated with reduced endometrial and ovarian risk, but affected carriers still require individualized prevention planning. [1][16]
- Record prior colorectal, endometrial, ovarian, and other Lynch-spectrum cancers before choosing surveillance and preventive surgery discussions. [16][17]
- Assess reproductive plans before recommending hysterectomy or oophorectomy; risk-reducing gynecologic surgery is generally considered after completion of childbearing. [5][8]
- Coordinate genetic counseling with gastroenterology, gynecology or gynecologic oncology, and the treating oncologist when cancer is already present. [5][17]

*Gene-informed counseling priorities after germline confirmation. [1][9][16]*

| Pathway | Risk pattern relevant to counseling | Practical implication |
| --- | --- | --- |
| MLH1 | Associated with comparatively higher Lynch-associated cancer risk in the cited clinical summary. [16] | Prioritize adherence to intensive colorectal surveillance and discuss gynecologic risk reduction when applicable. [5][16] |
| MSH2 or EPCAM-associated MSH2 pathway | MSH2 carriers have increased urinary tract cancer risk in the cited urologic literature. [12] | Review urinary tract cancer history and symptoms in addition to core colorectal and gynecologic prevention. [12][17] |
| MSH6 | Generally lower colorectal and other Lynch-associated risks than MLH1/MSH2; endometrial cancer may predominate over colorectal cancer in some families. [16][22] | Ensure gynecologic risk counseling is not deferred solely because colorectal risk may be lower. [22] |
| PMS2 | Lower colorectal, endometrial, and ovarian risk than several other MMR pathways, but risk is not absent. [1][16] | Maintain carrier surveillance and individualize surgical counseling to age, family history, and reproductive priorities. [1][16] |

## Use frequent colonoscopy to prevent and detect colorectal cancer

Colonoscopy is the primary actionable intervention for confirmed carriers.

Schedule colonoscopy every 1 to 2 years for confirmed Lynch syndrome carriers. The CDC advises beginning 2 to 5 years before the earliest colorectal cancer diagnosis in the family; European guidance cited in the evidence base uses 1- to 2-year intervals and gene-specific starting ages. [15][17]

Where using the cited gene-stratified protocol, begin at age 25 years for MLH1, MSH2, or EPCAM pathogenic-variant carriers and at age 30 years for MSH6 or PMS2 carriers; continue to age 75 years, then reassess. Earlier initiation is warranted when the family’s earliest colorectal cancer occurred before the applicable age threshold. [15]

Remove polyps during colonoscopy rather than treating surveillance as diagnostic observation alone. Lynch-associated colorectal neoplasia is often right-sided and may include flat premalignant lesions, supporting meticulous total-colon examination. [17][24]

Discuss aspirin chemoprevention as a separate shared decision rather than substituting it for colonoscopy. Long-term CAPP2 follow-up is cited as evidence for cancer prevention with aspirin in Lynch syndrome, but the excerpts do not establish a U.S. standard dose; a cited NICE scope notes that 75 to 300 mg is commonly offered outside the trial context. [1][9][15]
- At each surveillance visit, document interval colorectal symptoms, quality and completeness of the prior examination, polyp pathology, and the date of the next colonoscopy. [17][24]
- Do not lengthen the interval solely because a prior colonoscopy was normal; the cited prevention recommendations retain 1- to 2-year surveillance. [15][17]
- For a carrier who develops colorectal cancer, involve colorectal surgery in operative planning because risk of metachronous colorectal cancer and the extent of colectomy are relevant Lynch-specific considerations. [7]

*Colonoscopic timing framework for confirmed Lynch syndrome carriers. [15][17]*

| Clinical situation | Start or interval | Decision note |
| --- | --- | --- |
| Confirmed MLH1, MSH2, or EPCAM pathogenic variant | Start age 25 years in the cited protocol; repeat every 1 to 2 years. [15][17] | Start earlier when 2 to 5 years before the family’s earliest colorectal cancer requires it. [17] |
| Confirmed MSH6 or PMS2 pathogenic variant | Start age 30 years in the cited protocol; repeat every 1 to 2 years. [15][17] | Lower average risk does not eliminate surveillance. [1][16] |
| No prior colonoscopy since germline diagnosis | Arrange prompt baseline total colonoscopy, then assign a 1- to 2-year interval. [15][17] | Remove identified polyps during examination. [17] |
| Age 75 years or older | Reassess continuation in the cited protocol. [15] | Individualize according to health status, prior findings, and cancer history. |

## Address gynecologic risk directly and individualize extracolonic surveillance

Gynecologic prevention requires proactive counseling because screening is not reliably protective.

For carriers with a uterus and ovaries, discuss risk-reducing hysterectomy with bilateral salpingo-oophorectomy after childbearing is complete. In Lynch syndrome, prophylactic surgery has evidence of preventing endometrial and ovarian cancer and remains the most definitive risk-reducing option. [5][8][9]

Do not present transvaginal ultrasound and endometrial sampling as equivalent substitutes for surgery. Annual transvaginal ultrasound and endometrial sampling have variable sensitivity and adherence, and public-health guidance emphasizes that no simple, reliable screening test exists for gynecologic cancers in Lynch syndrome. [8][17]

Until definitive surgery, instruct patients to report abnormal uterine bleeding and other gynecologic cancer symptoms promptly rather than waiting for a surveillance interval. Symptom-triggered evaluation is particularly important because endometrial cancer is a major Lynch-associated malignancy. [16][17]

For extracolonic disease, make surveillance and symptom review gene- and family-history directed rather than applying a uniform battery of low-yield tests. Consider upper gastrointestinal evaluation in patients whose pedigree or clinical context suggests gastric cancer risk, and review hematuria or urinary tract symptoms carefully in MSH2 carriers because urinary tract cancer risk is increased in that subgroup. [11][12][17]
- Before bilateral salpingo-oophorectomy, document menopausal status, reproductive goals, and the consequences of surgical menopause. [5][8]
- For patients deferring surgery, establish a gynecologic follow-up plan and reinforce symptom-triggered assessment; neither surveillance nor symptom review eliminates ovarian cancer risk. [8][17]
- Inspect for and document sebaceous neoplasms or keratoacanthomas, which can occur in the Muir-Torre phenotype of Lynch syndrome. [16][17]

*Gynecologic prevention decisions in Lynch syndrome. [5][8][9][17]*

| Decision point | Recommended action | Key tradeoff |
| --- | --- | --- |
| Childbearing complete and uterus/ovaries present | Discuss risk-reducing hysterectomy with bilateral salpingo-oophorectomy. [5][8][9] | Provides the most definitive prevention of endometrial and ovarian cancer but ends fertility and may induce surgical menopause. [5][8] |
| Surgery deferred for reproductive or personal reasons | Use planned gynecologic follow-up and prompt evaluation of symptoms. [8][17] | Annual transvaginal ultrasound and endometrial sampling have variable sensitivity and adherence. [8] |
| Abnormal uterine bleeding or other concerning gynecologic symptoms | Perform prompt diagnostic evaluation rather than relying on routine surveillance timing. [17] | No simple, reliable gynecologic screening test is available for Lynch syndrome. [17] |

## References
1. Cancer Risk with the Lynch Syndrome PMS2 Gene | NEJM Clinician — clinician.nejm.org — https://clinician.nejm.org/cancer-risk-lynch-syndrome-pms2-gene-nejm-jw.NA37210
2. Identification and Survival of Carriers of Mutations in DNA Mismatch ... — www.nejm.org — https://www.nejm.org/doi/full/10.1056/NEJMoa053493
3. Prophylactic Surgery to Reduce the Risk of Gynecologic Cancers in ... — www.nejm.org — https://www.nejm.org/doi/full/10.1056/NEJMoa052627
4. Environmental and Heritable Factors in the Causation of Cancer — www.nejm.org — https://www.nejm.org/doi/full/10.1056/NEJM200007133430201
5. Prophylactic Surgery to Reduce the Risk of Gynecologic Cancers in the Lynch Syndrome | New England Journal of Medicine — www.nejm.org — https://www.nejm.org/doi/abs/10.1056/NEJMoa052627
6. Incidence of non-colorectal/endometrial malignancies in individuals ... — www.thelancet.com — https://www.thelancet.com/pdfs/journals/eclinm/PIIS2589-5370(25)00552-8.pdf
7. The Lancet Specialty Collections: Gastroenterology — www.thelancet.com — https://www.thelancet.com/collections/Gastroenterology?collexcode=107&subcollexcode=107102&ContribAuthorStored=Nelson%2C+Eric+J&Ppub=%5B20230404+TO+20250404%5D&ContentItemType=fla&startPage=2&pageSize=100
8. Lynch Syndrome and Gynecological Cancer Prevention | Cancer Genetics | Oncology and Carcinogenesis | Health sciences | Topics | Nature Index — www.nature.com — https://www.nature.com/nature-index/topics/l4/lynch-syndrome-and-gynecological-cancer-prevention
9. Risk-reducing hysterectomy and bilateral salpingo-oophorectomy in female heterozygotes of pathogenic mismatch repair variants: a Prospective Lynch Syndrome Database report | Genetics in Medicine — www.nature.com — https://www.nature.com/articles/s41436-020-01029-1
10. Screening for Colorectal Cancer: U.S. Preventive Services Task ... — www.acpjournals.org — https://www.acpjournals.org/doi/10.7326/0003-4819-149-9-200811040-00243
11. Clinical Factors Associated With Gastric Cancer in Individuals With Lynch Syndrome - ScienceDirect — www.sciencedirect.com — https://www.sciencedirect.com/science/article/abs/pii/S1542356519307451
12. Urinary Tract Cancer in Lynch Syndrome; Increased Risk in Carriers of MSH2 Mutations - ScienceDirect — www.sciencedirect.com — https://www.sciencedirect.com/science/article/abs/pii/S0090429515008249
13. Impact of genetic testing on endometrial cancer risk-reducing practices in women at risk for Lynch syndrome - ScienceDirect — www.sciencedirect.com — https://www.sciencedirect.com/science/article/abs/pii/S009082581200724X
14. The Clinical Features of Ovarian Cancer in Hereditary Nonpolyposis Colorectal Cancer - ScienceDirect — www.sciencedirect.com — https://www.sciencedirect.com/science/article/abs/pii/S0090825801962791
15. [PDF] national institute for health and care - NICE — www.nice.org.uk — https://www.nice.org.uk/guidance/htg557/documents/final-scope
16. Hereditary Nonpolyposis Colon Cancer (Lynch Syndrome) - StatPearls - NCBI Bookshelf — www.ncbi.nlm.nih.gov — https://www.ncbi.nlm.nih.gov/sites/books/NBK564511
17. Managing Risk for Cancers Related to Lynch Syndrome | Hereditary Colorectal (Colon) Cancer | CDC — www.cdc.gov — https://www.cdc.gov/colorectal-cancer-hereditary/managing-risk/index.html
18. Tumour MLH1 promoter region methylation testing is an effective pre-screen for Lynch Syndrome (HNPCC) - PMC — pmc.ncbi.nlm.nih.gov — https://pmc.ncbi.nlm.nih.gov/articles/PMC5159427
19. Performance of PREMM5, clinical criteria, and immunohistochemistry for MMR proteins in genetic risk assessment of Mexican patients with colorectal cancer — pmc.ncbi.nlm.nih.gov — https://pmc.ncbi.nlm.nih.gov/articles/PMC13436770
20. Lynch Syndrome - GeneReviews® - NCBI Bookshelf — www.ncbi.nlm.nih.gov — https://www.ncbi.nlm.nih.gov/books/NBK1211
21. Diagnosis of Lynch Syndrome and Strategies to Distinguish Lynch-Related Tumors from Sporadic MSI/dMMR Tumors — pmc.ncbi.nlm.nih.gov — https://pmc.ncbi.nlm.nih.gov/articles/PMC7865821
22. Genetic Testing for Lynch Syndrome, an Inherited Cancer of the Bowel, Endometrium, and Ovary — pmc.ncbi.nlm.nih.gov — https://pmc.ncbi.nlm.nih.gov/articles/PMC3349923
23. Genetics of Colorectal Cancer (PDQ®) - PDQ Cancer Information Summaries - NCBI Bookshelf — www.ncbi.nlm.nih.gov — https://www.ncbi.nlm.nih.gov/books/NBK126744
24. A Review of Hereditary Colorectal Cancers - StatPearls - NCBI Bookshelf — www.ncbi.nlm.nih.gov — https://www.ncbi.nlm.nih.gov/books/NBK538195

## Editorial note

Prepared from cited clinical literature using Astra's research workflow. Verify recommendations against current guidance and patient-specific factors.