Lynch syndrome risk calculator: carrier probability and hereditary colon cancer risk from a family pedigree

Short version. Lynch syndrome is an autosomal dominant condition caused by pathogenic variants in the DNA mismatch repair genes (MLH1, MSH2, MSH6, PMS2) or EPCAM deletions, and is the most common hereditary cause of colorectal cancer. Calculating Lynch risk uses a combination of clinical criteria (Amsterdam II, revised Bethesda), tumour testing (microsatellite instability, mismatch repair IHC), and quantitative models — principally MMRpro from the BayesMendel suite. MMRpro integrates pedigree data and, where available, tumour markers into a posterior carrier probability that is more sensitive than clinical criteria alone. Confirmed carriers enter enhanced surveillance and targeted cascade testing of relatives. Evagene runs MMRpro directly on the pedigree, with no re-entry, alongside BRCAPRO and PancPRO.

Lynch syndrome: clinical overview

Lynch syndrome, historically known as hereditary non-polyposis colorectal cancer (HNPCC), is the most common hereditary cause of colorectal cancer. It is an autosomal dominant condition driven by pathogenic germline variants in the DNA mismatch repair genes — primarily MLH1, MSH2, MSH6, and PMS2 — or by deletions of EPCAM that silence MSH2 through a read-through transcription mechanism.

In functional terms, the MMR machinery corrects base-base mismatches and small insertion/deletion loops that arise during DNA replication. Loss of MMR function causes accumulation of microsatellite instability — the clinically observable signature of a tumour developing on a Lynch background — and accelerated carcinogenesis in the tissues where the mutagenic burden is highest.

Identifying Lynch syndrome matters clinically because the downstream changes are substantial: enhanced colonoscopic surveillance starting in early adulthood, consideration of risk-reducing gynaecological surgery, specific tumour biology (MSI-high tumours respond well to immune checkpoint inhibitors in the metastatic setting), and cascade testing of at-risk relatives who can then be offered the same surveillance.

Cancer risks associated with Lynch syndrome

The Lynch tumour spectrum extends well beyond colorectal cancer. The qualitative picture is as follows, recognising that precise lifetime risks differ by gene and by reference cohort.

• Colorectal cancer. The defining cancer of the syndrome. Lifetime risk is substantially elevated, particularly for MLH1 and MSH2 carriers. Tumours tend to arise in the proximal colon, present earlier than sporadic cases, and have distinctive histological features such as tumour-infiltrating lymphocytes.
• Endometrial cancer. The second sentinel cancer. In many Lynch families, endometrial cancer is the first diagnosis that appears in the pedigree. Lifetime risk is substantial, particularly for MLH1 and MSH2 carriers.
• Ovarian cancer. Moderately elevated lifetime risk, often at younger ages than sporadic ovarian cancer. See our ovarian cancer family history page for how Lynch overlaps with BRCA-driven ovarian risk.
• Gastric cancer. Elevated, particularly intestinal-type adenocarcinoma. Regional baseline rates and dietary factors modulate the observed risk substantially.
• Small bowel cancer. Uncommon in the general population, enriched in Lynch kindreds.
• Urothelial cancer. Renal pelvis and ureter primarily, more strongly in MSH2 carriers.
• Hepatobiliary and pancreatic cancers. Moderately elevated. Pancreatic cancer overlaps with the hereditary pancreatic cancer differential; see our PancPRO guide.
• Brain cancer. Particularly glioblastoma in certain Lynch variants.
• Sebaceous skin tumours. The Muir-Torre variant of Lynch syndrome features sebaceous adenomas, sebaceous carcinomas, and keratoacanthomas alongside internal malignancy.

Risks differ by gene. MLH1 and MSH2 carriers generally have the highest colorectal and endometrial risks. MSH6 carriers have lower but still substantially elevated risks with a tendency towards later onset and a relatively greater endometrial contribution. PMS2 carriers have the lowest of the four gene-specific risks, though still meaningful and warranting surveillance.

From family history to diagnosis: the clinical workflow

Lynch syndrome diagnosis typically proceeds through a layered workflow, each step narrowing down who is tested and with what.

Not every step is required in every case. A recent tumour showing MSI-high and loss of MSH2/MSH6 on IHC may be enough to proceed directly to germline testing for MSH2 and EPCAM. An older family where no tumour specimen is accessible may rely on pedigree plus MMRpro to decide on germline testing eligibility. The workflow is a set of tools to reach for, not a fixed sequence.

Amsterdam II and revised Bethesda: what the criteria are

Amsterdam II criteria require three or more relatives with a Lynch-associated cancer, one a first-degree relative of the other two, spanning at least two successive generations, at least one diagnosis before age 50, and exclusion of familial adenomatous polyposis. Amsterdam II is specific — families that meet it are highly likely to have Lynch — but not sensitive. Many true Lynch kindreds fail Amsterdam II because they are small, because endometrial burden outweighs colorectal, or because older diagnoses lack documentation.

Revised Bethesda guidelines are broader and operate at the level of individual tumours. They flag tumours for MSI or IHC testing when features such as early-onset colorectal cancer (under 50), synchronous or metachronous Lynch-associated tumours, MSI-high histological features, or first-degree relatives with Lynch-associated cancer are present. Revised Bethesda is more sensitive than Amsterdam II but less specific, and still misses a meaningful fraction of carriers.

In modern pathology practice, many services run universal tumour MMR testing (MSI or IHC) on all colorectal and endometrial cancers, bypassing Bethesda as a triage step. This is substantially more sensitive and is now recommended by NICE, NCCN, and equivalent bodies in many jurisdictions.

MMRpro: quantitative pre-test probability

MMRpro is the Bayesian risk calculator in the BayesMendel suite that handles Lynch syndrome. It estimates the posterior probability of carrying a pathogenic variant in MLH1, MSH2, or MSH6 based on the pedigree and, optionally, tumour marker results. PMS2 coverage depends on implementation. See our dedicated MMRpro calculator guide for the detailed mechanics.

Clinically, MMRpro is most useful at two points in the workflow. Early, as a pre-test probability estimator to decide whether germline testing is indicated: a posterior above a defined threshold (commonly 5 percent, depending on commissioning framework) triggers testing. Later, as a way to integrate tumour markers with pedigree: when a tumour has been MSI-tested and IHC-stained, MMRpro combines that evidence with family history to produce a sharper estimate than either source alone.

Surveillance for confirmed carriers

Once a Lynch syndrome pathogenic variant is confirmed, surveillance is the core of clinical management. The specific programme depends on gene, age, and guideline, but the core components are consistent.

• Colonoscopy every one to two years from early adulthood. Starting age varies by gene — earlier for MLH1 and MSH2 (often 20 to 25), later for MSH6 and PMS2 — and by guideline.
• Gynaecological surveillance for women, with consideration of risk-reducing hysterectomy and bilateral salpingo-oophorectomy once childbearing is complete. The evidence base for annual transvaginal ultrasound and endometrial biopsy is weaker than for colonoscopy, and risk-reducing surgery is increasingly the primary strategy.
• Upper GI surveillance in selected families or gene-specific settings — typically gastroscopy at defined intervals, particularly in regions with higher baseline gastric cancer rates or where there is a family history of upper GI cancer.
• Urinary surveillance in specific settings, particularly for MSH2 carriers.
• Dermatological review for sebaceous tumours in Muir-Torre-suggestive kindreds.
• Chemoprevention — daily aspirin has randomised evidence for reducing colorectal cancer in Lynch carriers (the CAPP2 trial), and is increasingly recommended in contemporary guidelines with appropriate dose and duration counselling.

Cascade testing of first-degree relatives of a confirmed carrier is the other major clinical action, because each first-degree relative has a baseline 50 percent chance of carrying the same variant, and positive results open access to the same surveillance programme.

How Evagene integrates Lynch syndrome risk calculation

Evagene integrates MMRpro from the BayesMendel suite directly on the pedigree canvas. The same structured pedigree used to draw the family — with colorectal, endometrial, ovarian, gastric, urothelial, and other Lynch-spectrum cancers noted, ages of diagnosis, vital status, and (where available) tumour marker results recorded as annotations — is the input MMRpro needs. The model runs in an R sidecar process that calls the validated BayesMendel package, returning carrier probabilities and projected cancer risks that appear alongside the pedigree in the web interface.

A distinguishing feature for Lynch workflows is batch risk screening. Rather than requiring a clinician to remember to run MMRpro specifically, Evagene can run MMRpro alongside BRCAPRO, PancPRO, and Mendelian analyses across the full 200-plus disease catalogue in a single operation. For a pedigree with predominantly breast cancer plus a single colorectal case, MMRpro is run automatically, so a Lynch signal that might be missed in a breast-focused work-up is surfaced. See our broader hereditary cancer risk assessment guide for how batch screening fits the wider clinical workflow.

Evagene also supports AI interpretation with bring-your-own-key large language models. Once MMRpro has produced a Lynch posterior, the AI engine can draft a structured clinical summary covering key findings, family implications, data gaps, and screening recommendations — which a clinician reviews, edits, and signs. Traffic goes directly to your contracted LLM provider, not through an Evagene-hosted model, so clinical text handling stays within your existing risk assessment envelope.

For programmatic use, MMRpro is exposed through Evagene's REST API and MCP server, so downstream EHR integrations, research pipelines, and AI agents can retrieve Lynch carrier probabilities on a pedigree without a human in the loop. Docs are at evagene.net/help. Evagene is browser-based, zero install, and free during Alpha via the waiting list.

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