Table 3.

Genes Associated with Cancer Susceptibility to Consider in the Differential Diagnosis of BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer

Gene(s)Cancer Susceptibility SyndromeMOIAssociated Cancers / Distinctive Features
High-penetrance (high-risk) genes for breast cancer
ATMATM c.7271T>GADSpecific ATM pathogenic variants (e.g., c.7271T>G) are assoc w/high-penetrance breast cancer; heterozygosity for most other ATM pathogenic variants is assoc w/moderate-penetrance breast cancer (see below). 1
CDH1 Hereditary diffuse gastric cancer ADBreast cancer (lobular), diffuse gastric cancer. Majority of cancers occur before age 40 yrs.
PALB2 PALB2-related cancer susceptibility (OMIM 620442)ADBreast cancer ≤58%, 2 ovarian cancer, male breast cancer, pancreatic cancer
PTEN PTEN hamartoma tumor syndrome ADBreast cancer. Other cancers: thyroid, renal cell carcinoma, endometrial, colorectal. Multiple hamartomas, macrocephaly, trichilemmomas, papillomatous papules. Affected persons usually present by late 20s.
STK11 Peutz-Jeghers syndrome ADBreast cancer. Other cancers: GI, ovarian (mostly SCTAT), cervical (adenoma malignum), pancreatic, Sertoli cell testicular. GI polyposis, mucocutaneous pigmentation, hyperpigmented macules on fingers.
TP53 Li-Fraumeni syndrome ADBreast cancer (often premenopausal). Other cancers: soft tissue sarcoma, osteosarcoma, brain, adrenocortical carcinoma, leukemias. Early-onset & multiple primary cancers.
Moderate-penetrance (moderate-risk) genes for breast &/or ovarian cancer
ATM ATM-related cancer susceptibility (ATM heterozygotes; see Ataxia-Telangiectasia.)ADSpecific ATM pathogenic variants, most notably c.7271T>G, are assoc w/high-penetrance breast cancer; heterozygosity for most other ATM pathogenic variants is assoc w/moderate-penetrance breast cancer. ↑ risk for other types of tumors such as pancreatic cancer & prostate cancer.
BARD1 BARD1-related cancer susceptibility (OMIM 114480)ADBreast cancer
BRIP1 BRIP1-related cancer susceptibility (OMIM 605882)ADEpithelial ovarian cancer, 3 possible ↑ risk for breast cancer
CHEK2 CHEK2-related cancer susceptibility (OMIM 604373)ADBreast cancer 4
EPCAM
MLH1
MSH2
MSH6
PMS2 		Lynch syndrome ADOvarian cancer, slightly ↑ risk for breast cancer. Colorectal polyps, endometrial cancer, gastric cancer, & other cancers. 5
RAD51C RAD51C-related cancer susceptibility (OMIM 613399)ADOvarian cancer, possibly breast cancer (particularly ER/PR negative breast cancer)
RAD51D RAD51D-related cancer susceptibility (OMIM 614291)ADOvarian cancer, possibly breast cancer (particularly ER/PR negative breast cancer)

AD = autosomal dominant; ER = estrogen receptor; GI = gastrointestinal; MOI = mode of inheritance; PR = progesterone receptor; SCTAT = sex cord tumor with annular tubules

1.
2.
3.
4.

The CHEK2 variant c.1100delC (NM_007194​.3) is associated with an estimated two- to threefold increased breast cancer risk in women and a tenfold increased risk in men [CHEK2 Consortium 2004, Bernstein et al 2006, Weischer et al 2007].

5.

Note regarding PMS2: Although studies have suggested a 3% lifetime risk for ovarian cancer that is higher than the observed risk in the general population, studies that specifically examine risks among individuals with PMS2 pathogenic variants have not demonstrated a statistically significant relative increased risk for ovarian cancer.

From: BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer

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