Cancer Genetics Syndromes

Hereditary Breast & Ovarian Cancer (HBOC)

Autosomal dominant BRCA1 or BRCA2 pathogenic variants; high risks for breast & ovarian cancer; BRCA1 carriers have higher ovarian risk, BRCA2 carriers have added prostate, pancreatic & male breast cancer plus melanoma.

Li-Fraumeni Syndrome

Autosomal dominant TP53 mutation; extremely high, early-onset risk of multiple primaries including breast, brain, blood, bone (osteosarcoma) & adrenocortical carcinoma; whole-body MRI screening recommended.

ATM-associated Breast Cancer

Autosomal dominant single-allele ATM mutation raises breast (and pancreatic/ovarian/GI) cancer risk; biallelic mutations cause Ataxia-Telangiectasia.

CHEK2-associated Cancer

Autosomal dominant CHEK2 variant; elevated breast and kidney cancer risk.

PALB2-associated Cancer

Autosomal dominant PALB2 variant; increased breast, ovarian, pancreatic & prostate cancer; biallelic mutations cause Fanconi anemia.

BARD1-associated Breast Cancer

Autosomal dominant BARD1 mutation; heightened breast cancer risk.

BRIP1-associated Cancer

Autosomal dominant BRIP1 mutation; increases breast and ovarian cancer risk.

CDH1-related Hereditary Breast Cancer

Autosomal dominant CDH1 mutation outside HDGC context; raises lobular breast cancer risk.

Breast-associated Lynch Genes

MSH6 or PMS2 pathogenic variants confer breast cancer plus usual Lynch spectrum (CRC, endometrial, ovarian, GI).

RAD51C / RAD51D Breast & Ovarian Cancer

Autosomal dominant RAD51C or RAD51D mutation; increased breast & ovarian cancer; biallelic variants cause Fanconi anemia.

Neurofibromatosis Type 1

Autosomal dominant NF1 mutation; café-au-lait spots, neurofibromas, skeletal anomalies; cancer risks include breast, pheochromocytoma & paraganglioma.

Cowden Syndrome

Autosomal dominant PTEN mutation; macrocephaly, hamartomas, mucocutaneous lesions; cancers: breast, thyroid, uterine, colorectal & kidney.

Hereditary Diffuse Gastric Cancer (HDGC)

Autosomal dominant CDH1 (or CTNNA1) mutation; diffuse (signet-ring) gastric cancer & lobular breast cancer; prophylactic gastrectomy often recommended.

Lynch Syndrome – MLH1

Most penetrant Lynch gene; autosomal dominant MLH1 variants cause high risks of colorectal, endometrial, ovarian & other GI cancers.

Lynch Syndrome – MSH2/EPCAM

Second most penetrant Lynch genes; autosomal dominant; similar spectrum to MLH1 with high CRC & endometrial risk.

Lynch Syndrome – MSH6

Autosomal dominant; lower penetrance; colorectal, endometrial, ovarian, breast & other GI cancers.

Lynch Syndrome – PMS2

Least penetrant Lynch gene; autosomal dominant; colorectal, endometrial & ovarian cancer risk; no pancreatic cancer risk.

Classic Familial Adenomatous Polyposis (FAP)

Autosomal dominant APC mutation; hundreds of colorectal polyps by mid-teens, high CRC, upper GI & papillary thyroid cancer risk.

Attenuated FAP

Autosomal dominant APC mutation with ~30 polyps and later-onset colorectal cancer; papillary thyroid risk persists.

Peutz-Jeghers Syndrome

Autosomal dominant STK11 mutation; mucocutaneous freckling, small-intestinal polyps; near-100 % cancer penetrance (breast, pancreatic, ovarian, GI, testicular).

Von Hippel-Lindau Syndrome

Autosomal dominant VHL mutation; hemangioblastomas (CNS, retina), renal cell carcinoma, endolymphatic tumors & cystadenomas; highly penetrant.

WAGR Syndrome

Contiguous WT1/PAX6 deletion; Wilms tumor, Aniridia, Genitourinary anomalies & intellectual disability.

Beckwith-Wiedemann Syndrome

11p15.5 imprinting/UPD defect; macroglossia, omphalocele, overgrowth; increased Wilms tumor risk.

Birt-Hogg-Dubé Syndrome

Autosomal dominant FLCN mutation; fibrofolliculomas, lung cysts/pneumothorax & renal cell carcinoma.

Hereditary Papillary RCC

Autosomal dominant MET mutation; bilateral/multifocal type 1 papillary renal cell carcinoma.

Hereditary Leiomyomatosis & RCC

Autosomal dominant FH mutation; cutaneous & uterine leiomyomas and aggressive papillary RCC.

Multiple Endocrine Neoplasia Type 1

Autosomal dominant MEN1 mutation; parathyroid hyperplasia, pancreatic neuroendocrine & pituitary tumors.

Multiple Endocrine Neoplasia Type 2

Autosomal dominant RET mutation; medullary thyroid carcinoma, pheochromocytoma ± parathyroid disease.

MEN4 Syndrome

Autosomal dominant CDKN1B mutation; parathyroid, pancreatic & pituitary tumors; can include paraganglioma/pheochromocytoma.

Hereditary Paraganglioma/Pheochromocytoma

Autosomal dominant MAX or SDHA-SDHD mutations; catecholamine-secreting paragangliomas, pheochromocytomas, GIST & RCC; often skull-base or abdominal masses.

Hereditary Melanoma (CDKN2A)

Autosomal dominant CDKN2A mutations; high melanoma risk plus pancreatic & nervous-system tumors.

CDKN4-related Melanoma

Autosomal dominant CDK4 mutation; predisposes primarily to cutaneous melanoma.

BAP1 Tumor Predisposition

Autosomal dominant BAP1 mutation; melanocytic BAP1-inactivated nevus (pink dome papules), melanoma, mesothelioma & RCC.

MITF-associated Melanoma

Autosomal dominant MITF mutation; elevated melanoma & renal cell carcinoma risk.

MBD4-related Polyposis & Cancer

Autosomal recessive MBD4 deficiency; increased colorectal polyps, CRC, MDS/AML & melanoma due to mismatch-repair defect.

POT1 Tumor Predisposition

Autosomal dominant POT1 mutation; melanoma, chronic lymphocytic leukemia, glioma & angiosarcoma risk.

Gorlin Syndrome

Autosomal dominant PTCH1 or SUFU mutation; hundreds of basal cell carcinomas, jaw keratocysts, macrocephaly & medulloblastoma risk.

Xeroderma Pigmentosum

Autosomal recessive nucleotide-excision repair defect (XPA/XPC); extreme UV sensitivity, neurologic decline; early BCC, SCC & melanoma.

Bloom Syndrome

Autosomal recessive BLM mutation; growth deficiency, sun-sensitivity, immunodeficiency; cancers of blood, GI, skin & bone.

Fanconi Anemia

Autosomal recessive defects in FANCA-G, BRCA1/2, RAD51C, PALB2 etc.; bone-marrow failure, short stature, skeletal anomalies; high AML & SCC risk.

Hereditary Retinoblastoma

Autosomal dominant RB1 germline mutation; bilateral/multifocal retinoblastoma & soft-tissue sarcomas; avoid ionizing radiation.

Ataxia Telangiectasia

Autosomal recessive biallelic ATM mutation; cerebellar ataxia, telangiectasias, immunodeficiency; lymphoma, leukemia & solid-tumor risk; radiosensitive.

Tuberous Sclerosis Complex

Autosomal dominant TSC1/TSC2 mutations; hypomelanotic macules, cortical tubers, seizures, DD/ID; renal angiomyolipomas & lung LAM with cancer predisposition.