Breast Cancer Genes

Penetrance:

~55–72% lifetime, family/clinic-based (Kuchenbaecker 2017); ~50% by age 85 population-based (CARRIERS, Hu 2021). Cohort type matters — clinic estimates run higher.

Management:

Add annual breast MRI to mammography starting ~25–30; risk-reducing mastectomy is discussed; RRSO ~35–40 after childbearing. Screening intervals/surgery are set by genetics + GYN-onc, not the FP.

What to tell the patient:

Counsel that a positive result adds MRI screening, opens risk-reducing surgical options, and confers PARP-inhibitor eligibility if breast/ovarian cancer develops. Ovarian risk is what drives the RRSO conversation. Male carriers have prostate risk.

Referral:

Refer to genetic counseling. Do not start the surveillance/surgical workup yourself.

Kuchenbaecker et al., JAMA 2017 (penetrance); Hu et al. (CARRIERS), NEJM 2021 (population-based); ASCO-SSO germline testing guideline, Bedrosian JCO 2024.

Penetrance:

~45–69% lifetime, family/clinic-based (Kuchenbaecker 2017); ~50% by age 85 population-based (CARRIERS, Hu 2021).

Management:

Breast MRI added to mammography ~25–30; risk-reducing mastectomy discussed; RRSO ~40–45. Set by genetics/GYN-onc.

What to tell the patient:

Same HBOC counseling as BRCA1, but tumors are more often ER-positive. Emphasize male-relative implications: male breast cancer and aggressive prostate cancer, plus pancreatic risk. PARP-actionable.

Referral:

Refer to genetic counseling.

Kuchenbaecker et al., JAMA 2017; Hu et al. (CARRIERS), NEJM 2021; ASCO-SSO, Bedrosian JCO 2024.

Penetrance:

~41–60% lifetime, family-based; ~32% by age 85 population-based (CARRIERS, Hu 2021). Now firmly high-penetrance.

Management:

Breast MRI added; risk-reducing mastectomy discussed for higher-risk pedigrees; RRSO ~45–50 considered given moderate ovarian risk. Genetics-directed.

What to tell the patient:

Counsel this as near-BRCA in magnitude — patients often don't realize a non-BRCA gene can carry this much risk. Some ER-negative enrichment; pancreatic risk relevant to relatives.

Referral:

Refer to genetic counseling.

Variant note:

PARP-inhibitor activity is emerging (HRD gene) but NOT the established BRCA1/2 breast indication — do not counsel PALB2 as PARP-eligible on par with BRCA.

Yang et al., JCO 2020 (penetrance); Hu et al. (CARRIERS), NEJM 2021; ASCO-SSO, Bedrosian JCO 2024.

Penetrance:

Very high; breast cancer often very-early-onset (<30), ~54% by age 70. Overall LFS cancer risk >70% lifetime.

Management:

Whole-body MRI + brain MRI + breast MRI surveillance protocol. AVOID radiation where avoidable — prefer mastectomy over lumpectomy+radiotherapy, and minimize diagnostic radiation. Managed by an LFS program.

What to tell the patient:

The two FP-level points: (1) radiation avoidance, and (2) an absent family history does NOT exclude it — a meaningful fraction are de novo or mosaic. Very-early-onset or bilateral breast cancer should raise it.

Referral:

Refer to genetics / an LFS surveillance program.

Variant note:

De novo variants in ~7–20%; mosaicism reported. Clonal-hematopoiesis TP53 on a blood panel can mimic germline — confirm.

ASCO-SSO, Bedrosian JCO 2024; Li-Fraumeni consensus surveillance (Kratz et al., Clin Cancer Res 2017).

Penetrance:

High-penetrance; prospective-cohort lifetime female breast risk ~85–91% with ~50% penetrance by age 50 (GeneReviews; Tan 2012). Population-based estimates run lower — clinic ascertainment inflates the figure.

Management:

Breast MRI added; thyroid and endometrial surveillance. Genetics-directed.

What to tell the patient:

Look for the non-cancer phenotype that flags it in clinic: macrocephaly, trichilemmomas/oral papillomas, hamartomas, GI polyps. The syndrome is as much dermatologic/thyroid as breast.

Referral:

Refer to genetic counseling; dermatology/endocrine as phenotype dictates.

ASCO-SSO, Bedrosian JCO 2024; Tan et al., Clin Cancer Res 2012; GeneReviews: PTEN Hamartoma Tumor Syndrome (2026).

Penetrance:

~32–54% lifetime breast.

Management:

Breast MRI added; extensive GI/pancreatic/gynecologic surveillance program. Genetics + GI directed.

What to tell the patient:

Mucocutaneous pigmentation (lips, buccal mucosa) plus a history of intussusception or GI polyps is the clinical tell. Breast risk rides along with a broader GI-dominant syndrome.

Referral:

Refer to genetics / GI.

ASCO-SSO, Bedrosian JCO 2024; Beggs et al., Gut 2010 (PJS management).

Penetrance:

Lobular breast cancer ~37–42% lifetime (up to ~55% in some cohorts).

Management:

Breast MRI added (breast cancer is lobular histology). Prophylactic total gastrectomy is considered in the HDGC context — a surg-onc/genetics decision, not the FP's.

What to tell the patient:

Gastric risk usually dominates management. Point out the histology link — CDH1 breast cancer is lobular, and lobular cancers can be mammographically occult (another reason MRI matters).

Referral:

Refer to genetics / surgical oncology.

ASCO-SSO, Bedrosian JCO 2024; Blair et al., Lancet Oncol 2020 (HDGC guideline).

Penetrance:

~21–24% lifetime (moderate); population-based OR ~1.8 (CARRIERS, Hu 2021). Mostly ER-positive.

Management:

Consider annual breast MRI + mammography starting ~40, individualized by family history. NO risk-reducing mastectomy for the gene alone. Pancreatic surveillance only if family history warrants.

What to tell the patient:

Two counseling points: (1) biallelic ATM = ataxia-telangiectasia, so partner/offspring carrier status matters; (2) the specific variant matters — the c.7271T>G missense is atypically high-penetrance (~60%) and is managed more like a high-penetrance gene.

Referral:

Refer to genetics; stress that management is individualized enhanced screening, not automatic surgery.

Variant note:

ATM c.7271T>G behaves as high-penetrance (~60% by age 80) — a gene-level number understates it.

Hu et al. (CARRIERS), NEJM 2021; Dorling et al. (BCAC), NEJM 2021; ASCO-SSO, Bedrosian JCO 2024.

Penetrance:

~20–30% lifetime; truncating alleles (e.g., 1100delC) population OR ~2.5 (CARRIERS, Hu 2021). Mostly ER-positive; elevated contralateral risk.

Management:

Enhanced screening; breast MRI may be considered, individualized by family history. No prophylactic mastectomy for the gene alone.

What to tell the patient:

The most common finding on a PCP's multigene panel alongside ATM. Flag that low-penetrance missense alleles (e.g., Ile157Thr) behave near baseline — don't over-escalate a low-risk variant.

Referral:

Refer to genetics for variant interpretation before changing management.

Variant note:

Ile157Thr and other low-penetrance missense alleles behave near population baseline.

Hu et al. (CARRIERS), NEJM 2021; Dorling et al. (BCAC), NEJM 2021; ASCO-SSO, Bedrosian JCO 2024.

Penetrance:

Moderate; population-based OR ~2 (CARRIERS/BCAC). Enriched for ER-negative / triple-negative disease.

Management:

Enhanced screening; breast MRI may be considered, individualized. No prophylactic surgery for the gene alone.

What to tell the patient:

Note the ER-negative/triple-negative skew — screening is still imaging-based; there is no targeted therapy implication to promise.

Referral:

Refer to genetics.

Hu et al. (CARRIERS), NEJM 2021; Dorling et al. (BCAC), NEJM 2021.

Penetrance:

Moderate breast (OR ~1.5–2.3); ER-negative/triple-negative. Confers meaningful ovarian cancer risk.

Management:

Enhanced breast screening (MRI may be considered); the ovarian risk makes RRSO a discussion point — GYN-onc directed.

What to tell the patient:

Frame it as a two-organ result: modest breast risk plus a real ovarian-risk conversation. Ovarian screening is poor, so RRSO timing is the substantive question for genetics/GYN-onc.

Referral:

Refer to genetics; expect a GYN-onc RRSO discussion.

Hu et al. (CARRIERS), NEJM 2021; Dorling et al. (BCAC), NEJM 2021; ASCO-SSO, Bedrosian JCO 2024.

Penetrance:

Moderate breast (population-based OR ~1.8, BCAC 2021); ER-negative/triple-negative. Confers ovarian cancer risk.

Management:

Enhanced breast screening (MRI may be considered); ovarian risk makes RRSO a discussion point — GYN-onc directed.

What to tell the patient:

Same two-organ framing as RAD51C — the ovarian-risk/RRSO conversation is the clinically important part.

Referral:

Refer to genetics; expect a GYN-onc RRSO discussion.

Hu et al. (CARRIERS), NEJM 2021; Dorling et al. (BCAC), NEJM 2021; ASCO-SSO, Bedrosian JCO 2024.

Penetrance:

Modestly increased breast risk (OR ~1.9); risk is concentrated before age 50.

Management:

Earlier breast screening — mammography (± MRI) starting ~30, per the modest but earlier-onset risk. NF1 itself is usually a clinical diagnosis.

What to tell the patient:

The breast risk is often overlooked in patients already carrying an NF1 diagnosis — the actionable point is starting screening earlier than the general population.

Referral:

Genetics/neuro-oncology manage the broader NF1 tumor spectrum; the FP-level action is earlier breast screening.

Dorling et al. (BCAC), NEJM 2021; Uusitalo et al., J Clin Oncol 2016 (NF1 breast risk).

Penetrance:

Not established as actionable for breast cancer. (Founder variant 657del5 has been studied; evidence is insufficient to change management.)

Management:

Do NOT escalate breast screening on this result alone — insufficient evidence per NCCN. Manage by family history, not by the gene.

What to tell the patient:

The teaching point: a pathogenic result here is NOT an MRI trigger. Panels report genes that do not change breast management; recognizing them prevents over-screening.

Referral:

Genetics can interpret the variant, but the result itself does not change your screening plan.

NCCN Genetic/Familial High-Risk Assessment (genes below the actionable threshold); Hu et al. (CARRIERS), NEJM 2021 (no significant association).

Penetrance:

Not established as actionable for breast cancer.

Management:

Do NOT escalate breast screening on this result alone — insufficient evidence. Manage by family history.

What to tell the patient:

Another non-actionable panel result — no MRI trigger. Manage the family history, not the gene.

Referral:

Genetics for interpretation; screening plan unchanged by the result.

NCCN Genetic/Familial High-Risk Assessment (genes below the actionable threshold); Hu et al. (CARRIERS), NEJM 2021.

Penetrance:

Not established as actionable for breast cancer.

Management:

Do NOT escalate breast screening on this result alone — insufficient evidence. Manage by family history.

What to tell the patient:

Non-actionable for breast management — no MRI trigger from the gene.

Referral:

Genetics for interpretation; screening plan unchanged by the result.

NCCN Genetic/Familial High-Risk Assessment (genes below the actionable threshold); Hu et al. (CARRIERS), NEJM 2021.

Penetrance:

Not established as actionable for breast cancer; reported associations are not confirmed at a management-changing level.

Management:

Do NOT escalate breast screening on this result alone — insufficient evidence. Manage by family history.

What to tell the patient:

Reported in some studies but not confirmed to a level that changes management — no MRI trigger.

Referral:

Genetics for interpretation; screening plan unchanged by the result.

NCCN Genetic/Familial High-Risk Assessment (genes below the actionable threshold).

Penetrance:

Monoallelic/heterozygous carriers: insufficient evidence for increased breast cancer risk.

Management:

A heterozygous MUTYH result does NOT change breast screening. (Biallelic MUTYH = MUTYH-associated polyposis, a colorectal syndrome — a separate GI issue, not a breast indication.)

What to tell the patient:

Distinguish carrier (heterozygous) from biallelic. The common finding is a single carrier variant — no breast implication. Only biallelic disease is clinically significant, and that is colorectal, not breast.

Referral:

Genetics for interpretation; consider partner testing if biallelic status/offspring risk is in question.

NCCN Genetic/Familial High-Risk Assessment (MUTYH heterozygotes below the actionable threshold).