Inherited genetic variants do not cause cancer directly. Instead, they alter the risk that cancer will develop over a person's lifetime. The specific cancers associated with a variant depend on which gene is affected and what that gene normally does.

BRCA1 and BRCA2

BRCA1 and BRCA2 encode proteins that help repair double-strand breaks in DNA. Pathogenic variants in these genes are associated with significantly elevated lifetime risks of:

• Breast cancer (female and male)
• Ovarian cancer
• Pancreatic cancer
• Prostate cancer (particularly BRCA2)

Lifetime breast cancer risk estimates for BRCA1 pathogenic variant carriers range from approximately 50–72%; for BRCA2, approximately 45–69%. These figures vary across studies and depend on family history and other factors.

Lynch Syndrome Genes (Mismatch Repair)

Pathogenic variants in the mismatch repair genes — MLH1, MSH2, MSH6, PMS2, and EPCAM — cause Lynch syndrome. Associated cancers include:

• Colorectal cancer
• Endometrial (uterine) cancer
• Ovarian cancer
• Gastric cancer
• Urinary tract cancers
• Small bowel cancer
• Certain brain tumors (Turcot syndrome variant)

The specific risk profile depends on which gene is affected. MLH1 and MSH2 variants generally carry higher colorectal cancer risk than MSH6 or PMS2 variants.

TP53 — Li-Fraumeni Syndrome

TP53 encodes the p53 protein, often called the "guardian of the genome." Pathogenic germline variants cause Li-Fraumeni syndrome, associated with a very broad range of cancers including:

• Soft tissue sarcomas
• Osteosarcoma
• Breast cancer (often early onset)
• Brain tumors
• Adrenocortical carcinoma
• Leukemia

PALB2, ATM, CHEK2

These genes are involved in DNA repair pathways that overlap with BRCA function. Pathogenic variants are associated with moderately elevated breast cancer risk and, for some variants, increased risk of other cancers including pancreatic cancer.

APC — Familial Adenomatous Polyposis

Pathogenic variants in APC cause familial adenomatous polyposis (FAP), characterized by hundreds to thousands of colorectal polyps and a very high lifetime risk of colorectal cancer without preventive surgery. Variants in MUTYH cause a related condition called MUTYH-associated polyposis.

CDH1 — Hereditary Diffuse Gastric Cancer

Pathogenic variants in CDH1 are associated with hereditary diffuse gastric cancer and elevated risk of lobular breast cancer.

Why This Matters

Knowing which gene carries a pathogenic variant helps determine:

• Which cancers to screen for and at what age
• Whether preventive surgery or chemoprevention is appropriate
• Which family members should consider testing
• Whether targeted therapies (such as PARP inhibitors for BRCA-related cancers) may be relevant

At Genetic Insights, we help patients understand the specific cancer risks associated with their results and connect those risks to evidence-based management guidelines.

Key Takeaway: Different genes are linked to different cancer types. The specific gene affected determines which cancers to screen for, at what age, and what preventive options may be appropriate.

Sources: NCCN Guidelines — Genetic/Familial High-Risk Assessment; NCI BRCA Fact Sheet