Inherited Cancer Predisposition

Short version. Hereditary cancer-predisposition syndromes are dominated by germline tumour-suppressor variants whose biallelic inactivation, somatically completed in tumour-precursor cells, drives malignancy. The main syndromes are HBOC (BRCA1/2 plus PALB2, ATM, CHEK2 and related genes), Lynch syndrome (the mismatch-repair genes), FAP and MAP (APC, MUTYH), Li-Fraumeni (TP53), Cowden (PTEN), Peutz-Jeghers (STK11), juvenile polyposis (BMPR1A, SMAD4), HDGC (CDH1), and several rarer syndromes (VHL, MEN1, MEN2, NF1, NF2, TSC, RB1). Lifetime-risk estimates derive from large peer-reviewed cohorts; published surveillance frameworks are issued by NCCN, ESMO, EHTG, and NICE.

Educational positioning. Evagene is an academic, research, and educational pedigree modelling platform. Where this page references a published surveillance protocol or guideline, the framing is consistently the published guidelines describe X, not the patient should X. The platform documents family-history information, applies published risk-model algorithms (BRCAPRO, MMRpro, PancPRO, Tyrer-Cuzick IBIS-style approximation, Claus, Couch, Frank, Manchester, Gail, Amsterdam II / revised Bethesda representations), and exports CanRisk pedigree files for off-platform BOADICEA. Outputs are illustrative and for research / education purposes only. Evagene does not issue surveillance, screening, testing, referral, or treatment recommendations and is not a medical device.

Hereditary breast and ovarian cancer (HBOC)

Genes: BRCA1 (17q21), BRCA2 (13q12), PALB2 (16p12), ATM (11q22), CHEK2 (22q12); also rarer contributors including BARD1, RAD51C, RAD51D, BRIP1.
Inheritance: autosomal dominant.
Principal cancers: breast (female and male), ovarian (including fallopian tube and primary peritoneal), pancreatic, prostate, plus melanoma in BRCA2.

The lifetime breast-cancer risk estimates that anchor most teaching come from large prospective and retrospective cohorts. Antoniou et al. 2003 (Am J Hum Genet 72:1117) conducted a meta-analysis of 22 unselected studies and reported cumulative breast cancer risks to age 70 of approximately 65% (95% CI 44–78%) for BRCA1 carriers and 45% (31–56%) for BRCA2 carriers, with ovarian-cancer risks of approximately 39% (18–54%) and 11% (2.4–19%) respectively. The prospective cohort of Kuchenbaecker et al. 2017 (JAMA 317:2402) followed 6,036 BRCA1 and 3,820 BRCA2 carriers and reported cumulative breast-cancer risks to age 80 of 72% (BRCA1) and 69% (BRCA2), with ovarian-cancer risks of 44% and 17% respectively, and contralateral breast-cancer risks of 40% and 26% at 20 years post-diagnosis. Domchek et al. 2010 (JAMA 304:967) demonstrated the magnitude of risk reduction associated with risk-reducing salpingo-oophorectomy and bilateral mastectomy in BRCA1/2 carriers. PALB2 cumulative breast-cancer risk to age 80 has been reported around 53% in family-based studies. ATM heterozygotes carry approximately twofold relative risk; CHEK2 c.1100delC carriers approximately twofold.

Published guideline frameworks describing HBOC management include NCCN Genetic / Familial High-Risk Assessment: Breast, Ovarian, Pancreatic; ESMO Clinical Practice Guidelines on hereditary breast cancer; and NICE CG164 (familial breast cancer). The published guidelines describe enhanced surveillance regimens and risk-reducing options; they are issued by guideline-development bodies and treating clinicians make individual decisions in consultation with patients. Evagene does not issue or replicate guideline-driven recommendations.

Family-history modelling for HBOC: see BRCAPRO for Bayesian carrier-probability estimation; breast-cancer family-history scoring and ovarian-cancer family-history scoring for the Claus / Couch / Frank / Manchester / NICE family-history models; and BOADICEA vs BRCAPRO for the architectural comparison and the CanRisk file-export bridge to off-platform BOADICEA at canrisk.org.

Lynch syndrome (hereditary non-polyposis colorectal cancer)

Genes: MLH1 (3p22), MSH2 (2p21), MSH6 (2p16), PMS2 (7p22); plus EPCAM 3′ deletions causing constitutional MSH2 silencing.
Inheritance: autosomal dominant.
Principal cancers: colorectal, endometrial, ovarian, gastric, small bowel, urothelial (upper urinary tract), hepatobiliary, pancreatic, sebaceous (Muir-Torre); central nervous system (Turcot).

Two foundational sets of published criteria are used to describe families with a clinical pattern consistent with Lynch syndrome: the Amsterdam II criteria (Vasen et al. 1999, Gastroenterology 116:1453) and the revised Bethesda guidelines (Umar et al. 2004, J Natl Cancer Inst 96:261). The Amsterdam II framework specifies a family-history pattern (three or more relatives with HNPCC-associated cancers, two successive generations, one diagnosed before age 50, FAP excluded). The revised Bethesda guidelines describe tumour-based criteria (early-onset colorectal cancer, MSI-H histology, synchronous / metachronous tumours) used to identify tumours warranting MMR-protein immunohistochemistry or microsatellite-instability testing as part of a published diagnostic workup. Evagene’s representation of these criteria is for educational and family-history modelling purposes; the platform does not perform or order tumour-based molecular testing.

Lifetime cumulative cancer-risk estimates vary by gene. The Prospective Lynch Syndrome Database (PLSD; Møller et al. 2018, Gut 67:1306) gives gene-stratified penetrance estimates: MLH1 and MSH2 carriers show high colorectal and endometrial risk; MSH6 shows lower colorectal but substantial endometrial risk; PMS2 shows the lowest organ-specific penetrances of the four. The European Hereditary Tumour Group has published surveillance guidance (Vasen et al. 2013, Gut 62:812 and successor documents). Family-history modelling: see the MMRpro calculator for Bayesian carrier-probability estimation across the four MMR genes, and the Lynch syndrome family-history calculator for representations of Amsterdam II and revised Bethesda criteria.

Familial adenomatous polyposis (FAP) and attenuated FAP

Gene: APC (5q22).
Inheritance: autosomal dominant; ~25% of cases arise from de novo variants.
Principal cancers: colorectal (lifetime risk approaching 100% in classical FAP without intervention), duodenal (especially periampullary), thyroid, hepatoblastoma, desmoid tumours; CHRPE, osteomas, supernumerary teeth as Gardner-syndrome features.

Classical FAP presents with hundreds to thousands of adenomatous polyps from the second decade; attenuated FAP shows fewer polyps and later onset, often with 5′- and 3′-end APC variants. The published European Hereditary Tumour Group guidelines on FAP and attenuated FAP (Aretz et al. 2018, Eur J Hum Genet) describe surveillance and management frameworks; NCCN colorectal cancer screening guidelines also cover this syndrome. Genotype-phenotype correlations are well documented — codon 1309 variants associate with severe phenotype.

MUTYH-associated polyposis (MAP)

Gene: MUTYH (1p34).
Inheritance: autosomal recessive (biallelic carriers).
Principal cancers: colorectal cancer with attenuated polyposis phenotype overlapping FAP; duodenal polyps; possible modest elevation of breast and ovarian risk in monoallelic carriers (debated).

MAP is the canonical example of a recessive cancer-predisposition syndrome among the dominant majority. Biallelic carriers show an FAP-like phenotype with somatic G:C→T:A transversions in APC reflecting the loss of base-excision repair of 8-oxoguanine. European founder variants Y179C and G396D dominate the variant spectrum.

Li-Fraumeni syndrome

Gene: TP53 (17p13).
Inheritance: autosomal dominant; substantial fraction of cases arise from de novo variants.
Principal cancers: sarcoma (osteosarcoma, soft-tissue), pre-menopausal breast cancer, brain tumours (glioma, choroid plexus carcinoma), adrenocortical carcinoma; the ‘core’ LFS spectrum. Numerous additional tumour types occur with elevated frequency.

Lifetime cumulative cancer risk in TP53 germline carriers exceeds 70% in classical Li-Fraumeni families and approaches 100% by age 70. The 2020 European reference network ERN-GENTURIS Li-Fraumeni guidelines (Frebourg et al. 2020, Eur J Hum Genet 28:1379) consolidate the published surveillance and management framework. The Toronto protocol (Villani et al.) is one published whole-body surveillance approach with reported overall-survival benefit in case-cohort studies.

Cowden syndrome / PTEN hamartoma tumour syndrome

Gene: PTEN (10q23).
Inheritance: autosomal dominant.
Principal cancers: breast, thyroid (follicular), endometrial, renal cell carcinoma, colorectal, melanoma; macrocephaly, mucocutaneous lesions, intellectual disability spectrum (Bannayan-Riley-Ruvalcaba) as syndromic features.

PTEN haploinsufficiency contributes to the phenotype, in contrast to the strict two-hit pattern of most tumour suppressors — covered on the oncogenes and tumour suppressors page. Lifetime breast-cancer risk in PTEN carriers exceeds 80% in published cohorts (Tan et al. 2012). Published surveillance frameworks come from NCCN and the European reference network for genetic tumour syndromes.

Peutz-Jeghers syndrome

Gene: STK11 / LKB1 (19p13).
Inheritance: autosomal dominant.
Principal features and cancers: mucocutaneous hyperpigmentation (lips, buccal mucosa, fingertips); hamartomatous polyposis of the small bowel and colon (with intussusception risk); markedly elevated risk of breast, gastrointestinal (gastric, small bowel, colorectal, pancreatic), gynaecological (cervical adenoma malignum, sex cord tumours with annular tubules), and lung cancer.

Cumulative cancer risk to age 70 has been reported around 80%. The European Hereditary Tumour Group / Mallorca-group consensus paper (Beggs et al. 2010, Gut 59:975) and updated successor documents constitute the published surveillance framework.

Juvenile polyposis syndrome

Genes: BMPR1A (10q23), SMAD4 (18q21).
Inheritance: autosomal dominant.
Principal cancers: colorectal, gastric, small bowel, pancreatic. SMAD4 carriers also show overlapping hereditary haemorrhagic telangiectasia (HHT) features; combined JPS-HHT phenotype has implications for surveillance of arteriovenous malformations.

Hereditary diffuse gastric cancer (HDGC)

Gene: CDH1 (16q22) encoding E-cadherin; rarer contributions from CTNNA1.
Inheritance: autosomal dominant.
Principal cancers: diffuse-type (signet-ring) gastric cancer; lobular breast cancer in female CDH1 carriers; cleft lip / palate as associated developmental finding in some families.

Published criteria for considering CDH1 testing originate from the International Gastric Cancer Linkage Consortium (IGCLC); the 2020 IGCLC update (Blair et al. 2020, Lancet Oncol 21:e386) is the current published reference. The published guidelines describe options including endoscopic surveillance and risk-reducing total gastrectomy; choices are made between treating clinicians and patients.

Von Hippel-Lindau syndrome

Gene: VHL (3p25).
Inheritance: autosomal dominant.
Principal features: retinal and CNS haemangioblastomas, clear-cell renal carcinoma, phaeochromocytoma, pancreatic neuroendocrine tumours, endolymphatic-sac tumours, epididymal cystadenomas. Genotype-phenotype correlations distinguish VHL type 1 (no phaeochromocytoma), type 2A (with phaeochromocytoma, low RCC risk), 2B (high RCC risk) and 2C (phaeochromocytoma only).

Multiple endocrine neoplasia (MEN1, MEN2)

MEN1 (gene MEN1, 11q13): parathyroid adenoma, pancreatic neuroendocrine tumours (gastrinoma, insulinoma), anterior pituitary adenoma; lipomas and angiofibromas as cutaneous features.
MEN2 (gene RET, 10q11): medullary thyroid carcinoma (MTC; near-100% lifetime risk), phaeochromocytoma, primary hyperparathyroidism (MEN2A); MEN2B adds mucosal neuromas, intestinal ganglioneuromatosis, marfanoid habitus and earlier MTC onset.

RET is the rare example of a germline-activating oncogene driving a hereditary syndrome — specific codon variants determine the MEN2 subtype. The published American Thyroid Association MTC guidelines stratify recommendations by RET codon. As above, Evagene reports family-history features for educational and pedigree-modelling purposes; clinical decisions are made off-platform.

Neurofibromatoses and tuberous sclerosis

NF1 (17q11) — neurofibromatosis type 1; café-au-lait macules, axillary freckling, Lisch nodules, neurofibromas, plexiform neurofibromas, optic pathway gliomas, malignant peripheral nerve sheath tumours, breast cancer (women under 50). NF1 encodes neurofibromin, a RAS GAP.
NF2 (22q12) — bilateral vestibular schwannomas, meningiomas, ependymomas; encodes merlin.
Tuberous sclerosis — genes TSC1 (9q34) and TSC2 (16p13); cortical tubers, subependymal giant cell astrocytoma (SEGA), facial angiofibromas, renal angiomyolipoma, pulmonary lymphangioleiomyomatosis, cardiac rhabdomyoma; mTOR-pathway hyperactivation underlies the phenotype.

Retinoblastoma

Gene: RB1 (13q14).
Inheritance: autosomal dominant (in the heritable form); ~40% of cases are heritable, ~60% non-heritable.
Principal cancers: retinoblastoma in early childhood (typically bilateral / multifocal in the heritable form, unilateral / unifocal in non-heritable); secondary primary cancers in heritable retinoblastoma survivors include osteosarcoma, soft-tissue sarcoma, cutaneous melanoma, and lung cancer.

RB1 is the gene whose study yielded Knudson’s two-hit hypothesis; see the oncogenes and tumour suppressors page for the mechanistic context.

Family-history modelling on a single pedigree

The pedigree is the artefact through which inherited cancer-predisposition syndromes are recognised. Evagene’s hereditary cancer risk assessment page describes the suite of published risk-model algorithms operating on a single drawn pedigree:

BayesMendel. BRCAPRO (BRCA1/2 carrier probability), MMRpro (MMR carrier probability), PancPRO (familial pancreatic cancer modelling).
Family-history scoring. Claus 1994 (breast); Couch 1997, Frank 2002, Manchester scoring system (BRCA likelihood); NICE CG164 / NG101 family-history triage representation; Amsterdam II / revised Bethesda representation for Lynch.
Empirical risk. Gail NCI BCRAT 1989; Tyrer-Cuzick (IBIS-style approximation of the published Tyrer / Duffy / Cuzick 2004 algorithm; not the official IBIS Breast Cancer Risk Evaluator binary).
CanRisk file export to canrisk.org for off-platform BOADICEA computation. BOADICEA is licensed by the University of Cambridge and is not bundled in Evagene; Evagene exports a ##CanRisk 2.0 pedigree file the user uploads at canrisk.org. CanRisk v3 (2025), with BOADICEA breast cancer v7 and ovarian v3, introduced UK-ethnicity-specific parameters and other fields that the v2.0 export does not carry; for those v3 fields, enter the family directly at canrisk.org.

All outputs are illustrative and for research / education purposes. The platform does not generate surveillance, screening, testing, referral, or treatment recommendations; the published guidelines describe such options and clinicians make decisions with patients off-platform.

Selected sources

Antoniou A, Pharoah PD, Narod S, et al. Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations. Am J Hum Genet 2003; 72:1117. PMID 12677558.
Kuchenbaecker KB, Hopper JL, Barnes DR, et al. Risks of breast, ovarian, and contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. JAMA 2017; 317:2402. PMID 28632866.
Domchek SM, Friebel TM, Singer CF, et al. Association of risk-reducing surgery in BRCA1 or BRCA2 mutation carriers with cancer risk and mortality. JAMA 2010; 304:967. PMID 20810374.
Vasen HF, Watson P, Mecklin JP, Lynch HT. New clinical criteria for hereditary nonpolyposis colorectal cancer (Amsterdam II). Gastroenterology 1999; 116:1453. PMID 10348829.
Umar A, Boland CR, Terdiman JP, et al. Revised Bethesda guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst 2004; 96:261. PMID 14970275.
Møller P, Seppala T, Bernstein I, et al. Cancer incidence and survival in Lynch syndrome carriers (Prospective Lynch Syndrome Database). Gut 2018; 67:1306. PMID 29575550.
Aretz S, Hes FJ, Hes Vet al. European guidelines from the EHTG and ESCP for FAP / attenuated FAP. Eur J Hum Genet 2018. PMID 30317547.
Frebourg T, Bajalica Lagercrantz S, Oliveira C, et al. Guidelines for the Li-Fraumeni and heritable TP53-related cancer syndromes. Eur J Hum Genet 2020; 28:1379. PMID 32457520.
Beggs AD, Latchford AR, Vasen HF, et al. Peutz-Jeghers syndrome: a systematic review and recommendations for management. Gut 2010; 59:975. PMID 20581245.
Blair VR, McLeod M, Carneiro F, et al. Hereditary diffuse gastric cancer: updated clinical practice guidelines. Lancet Oncol 2020; 21:e386. PMID 32864856.
NCCN Genetic / Familial High-Risk Assessment Guidelines — nccn.org.
NICE CG164 (familial breast cancer) and NG101 — nice.org.uk/guidance/cg164.
GeneReviews (NCBI Bookshelf), entries on each syndrome — ncbi.nlm.nih.gov/books.