Hereditary breast cancer: genes and variants
Explore variant evidence for Hereditary breast cancer across 17 analyzed proteins (PALB2, TP53, CHEK2, ATM, BARD1 and 12 more). Linked ClinVar records include 23 pathogenic or likely pathogenic variants, 6,066 variants of uncertain significance and 821 with conflicting classifications.
Coverage includes proteins already analyzed in CATVariant, not every gene involved in this condition. Database links are associations, not an assessment of clinical gene–disease validity. Computable evidence prioritizes variants for expert review and does not reclassify them. Source labels are pooled across this disease family.
Data updated 2026-10-10. Automated aggregation, not a clinical review date.
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Genes linked to Hereditary breast cancer
PALB2: Partner and localizer of BRCA2
It physically links BRCA1 and BRCA2 and helps recruit BRCA2-RAD51 repair machinery to DNA double-strand breaks. Heterozygous loss-of-function variants substantially increase breast and pancreatic cancer risk, while biallelic variants cause Fanconi anemia subtype N.
5 ClinVar pathogenic / likely pathogenic and 1,846 uncertain variants in PALB2 have source records linked to Hereditary breast cancer. Association strength is not clinical gene validity.
TP53: Cellular tumor antigen p53
It coordinates transcriptional responses to DNA damage and other cellular stresses, promoting cell-cycle arrest, senescence, DNA repair, or apoptosis when appropriate. Loss of this tumor-suppressive control is one of the most common events in cancer, while germline pathogenic variants cause Li-Fraumeni syndrome.
5 ClinVar pathogenic / likely pathogenic and 21 uncertain variants in TP53 have source records linked to Hereditary breast cancer. Association strength is not clinical gene validity.
CHEK2: Serine/threonine-protein kinase Chk2
It propagates DNA-damage checkpoint signals to proteins controlling cell-cycle arrest, repair, and apoptosis. Germline loss-of-function variants confer moderate cancer susceptibility, especially for breast cancer, while risk estimates depend on the specific allele and family context.
3 ClinVar pathogenic / likely pathogenic and 1,371 uncertain variants in CHEK2 have source records linked to Hereditary breast cancer. Association strength is not clinical gene validity.
ATM: Serine-protein kinase ATM
It is activated by DNA double-strand breaks and coordinates checkpoint arrest, repair, and apoptosis through phosphorylation of numerous targets. Biallelic loss causes ataxia-telangiectasia, while heterozygous pathogenic variants increase susceptibility to several cancers.
3 ClinVar pathogenic / likely pathogenic and 95 uncertain variants in ATM have source records linked to Hereditary breast cancer. Association strength is not clinical gene validity.
BARD1: BRCA1-associated RING domain protein 1
It forms a heterodimer with BRCA1 that supports homologous recombination, DNA-damage signaling, and ubiquitin-dependent regulation at damaged chromatin. Germline loss-of-function variants confer increased breast-cancer susceptibility, particularly for some aggressive subtypes.
2 ClinVar pathogenic / likely pathogenic and 1,507 uncertain variants in BARD1 have source records linked to Hereditary breast cancer. Association strength is not clinical gene validity.
BRIP1: Fanconi anemia group J protein
It unwinds DNA structures and works with BRCA1 and the Fanconi-anemia pathway to repair damaged replication intermediates and interstrand crosslinks. Biallelic loss causes Fanconi anemia group J, while heterozygous loss-of-function variants increase ovarian-cancer risk.
1 ClinVar pathogenic / likely pathogenic and 1,835 uncertain variants in BRIP1 have source records linked to Hereditary breast cancer. Association strength is not clinical gene validity.
PIK3CA: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform
Its p110-alpha catalytic activity generates PIP3 and activates AKT-dependent growth, survival, and metabolic signaling downstream of many receptors. Activating variants are frequent cancer drivers and, when present mosaically during development, can cause PIK3CA-related overgrowth spectrum.
1 ClinVar pathogenic / likely pathogenic and 4 uncertain variants in PIK3CA have source records linked to Hereditary breast cancer. Association strength is not clinical gene validity.
KRAS: GTPase KRas
A small GTPase that acts as a molecular switch in the RAS-MAPK signaling pathway. By cycling between GDP- and GTP-bound states, it relays growth and survival signals, and activating KRAS variants are common drivers of cancer.
1 ClinVar pathogenic / likely pathogenic and 1 uncertain variants in KRAS have source records linked to Hereditary breast cancer. Association strength is not clinical gene validity.
EPCAM: Epithelial cell adhesion molecule
It supports epithelial organization and signaling at cell-cell interfaces. Deletions extending through its 3-prime end can silence neighboring MSH2 and cause Lynch syndrome, while biallelic loss-of-function variants cause congenital tufting enteropathy.
1 ClinVar pathogenic / likely pathogenic and 0 uncertain variants in EPCAM have source records linked to Hereditary breast cancer. Association strength is not clinical gene validity.
PTEN: Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN
A lipid and protein phosphatase that removes phosphate groups from signaling molecules, especially PIP3. By opposing the PI3K-AKT pathway, it limits cell growth and survival signals, and PTEN variants are associated with Cowden syndrome and multiple cancers.
1 ClinVar pathogenic / likely pathogenic and 0 uncertain variants in PTEN have source records linked to Hereditary breast cancer. Association strength is not clinical gene validity.
PPM1D: Protein phosphatase 1D
It turns off DNA-damage signaling by dephosphorylating p53-pathway and checkpoint proteins after cellular stress. Truncating mutations that stabilize the protein occur in clonal hematopoiesis and cancer and can confer a selective advantage after genotoxic therapy.
0 ClinVar pathogenic / likely pathogenic and 2 uncertain variants in PPM1D have source records linked to Hereditary breast cancer. Association strength is not clinical gene validity.
BRCA1: Breast cancer type 1 susceptibility protein
It coordinates DNA-damage signaling and homologous-recombination repair while helping protect stalled replication forks and chromosome integrity. Germline loss-of-function variants strongly predispose to breast and ovarian cancer and increase risk for several other malignancies.
0 ClinVar pathogenic / likely pathogenic and 1 uncertain variants in BRCA1 have source records linked to Hereditary breast cancer. Association strength is not clinical gene validity.
BRCA2: Breast cancer type 2 susceptibility protein
It loads RAD51 onto damaged DNA to enable homologous recombination and also protects stressed replication forks from degradation. Germline loss-of-function variants strongly predispose to breast, ovarian, prostate, pancreatic, and other cancers.
0 ClinVar pathogenic / likely pathogenic and 1 uncertain variants in BRCA2 have source records linked to Hereditary breast cancer. Association strength is not clinical gene validity.
MLH1: DNA mismatch repair protein Mlh1
The protein partners with PMS2 to form MutL alpha, a core complex in post-replicative DNA mismatch repair. By helping correct copying errors in DNA, MLH1 protects genome stability, and inherited MLH1 variants are a major cause of Lynch syndrome.
0 ClinVar pathogenic / likely pathogenic and 0 uncertain variants in MLH1 have source records linked to Hereditary breast cancer. Association strength is not clinical gene validity.
CDH1: Cadherin-1
Its E-cadherin-mediated adhesion preserves epithelial architecture and suppresses inappropriate cell detachment and invasion. Germline loss-of-function variants cause hereditary diffuse gastric cancer syndrome and substantially increase diffuse gastric and lobular breast-cancer risk.
0 ClinVar pathogenic / likely pathogenic and 169 uncertain variants in CDH1 have source records linked to Hereditary breast cancer. Association strength is not clinical gene validity.
RAD50: DNA repair protein RAD50
It provides ATP-dependent DNA tethering within the MRE11-RAD50-NBN complex and helps organize detection and processing of double-strand breaks. Biallelic loss-of-function variants can cause a Nijmegen-breakage-syndrome-like disorder with chromosome instability and developmental abnormalities.
0 ClinVar pathogenic / likely pathogenic and 16 uncertain variants in RAD50 have source records linked to Hereditary breast cancer. Association strength is not clinical gene validity.
AKT1: RAC-alpha serine/threonine-protein kinase
It integrates PI3K-dependent growth-factor signals to promote cell survival, proliferation, glucose metabolism, and protein synthesis. Somatic activating variants occur in multiple cancers, while mosaic activation, especially E17K, causes Proteus syndrome.
0 ClinVar pathogenic / likely pathogenic and 7 uncertain variants in AKT1 have source records linked to Hereditary breast cancer. Association strength is not clinical gene validity.
Weakly linked (only a few uncertain records): ESR1, RAD51, ERBB2, ABCC1, CASP8, FANCD2, MLH3, NBN and 5 more.
Where Hereditary breast cancer variants cluster
- PALB2 Required for its oligomerization and is importan (positions 1–160): 4 of 5 ClinVar pathogenic / likely pathogenic variants, 5.9× more than its size predicts.
- TP53 Interaction with AXIN1 (positions 116–292): 5 of 5 ClinVar pathogenic / likely pathogenic variants, 2.2× more than its size predicts.
ClinVar pathogenic and likely pathogenic variants linked to Hereditary breast cancer
| Variant | Position | Protein part | Clinical label |
|---|---|---|---|
| BARD1 C71Y | 71 | RING-type | Pathogenic / likely pathogenic (★★) |
| KRAS G12A | 12 | Pathogenic / likely pathogenic (★★) | |
| CHEK2 G167R | 167 | FHA | Pathogenic / likely pathogenic (★★) |
| PALB2 M1V | 1 | Required for its oligomerization and is importan | Pathogenic / likely pathogenic (★★) |
| PALB2 M1R | 1 | Required for its oligomerization and is importan | Pathogenic / likely pathogenic (★★) |
| PALB2 M1T | 1 | Required for its oligomerization and is importan | Pathogenic / likely pathogenic (★★) |
| TP53 S241F | 241 | DNA binding | Pathogenic / likely pathogenic (★★) |
| ATM M1I | 1 | Pathogenic / likely pathogenic (★★) | |
| TP53 I195T | 195 | DNA binding | Pathogenic / likely pathogenic (★★) |
| TP53 R273G | 273 | DNA binding | Pathogenic / likely pathogenic (★★) |
| EPCAM M1V | 1 | Pathogenic / likely pathogenic (★★) | |
| TP53 V143M | 143 | DNA binding | Pathogenic / likely pathogenic (★★) |
| TP53 D281V | 281 | DNA binding | Pathogenic / likely pathogenic (★★) |
| BRIP1 Q169H | 169 | Helicase ATP-binding | Pathogenic / likely pathogenic (★★) |
| PIK3CA N345K | 345 | C2 PI3K-type | Pathogenic / likely pathogenic (★★) |
| PALB2 M1I | 1 | Required for its oligomerization and is importan | Pathogenic / likely pathogenic (★) |
| PTEN F90L | 90 | Phosphatase tensin-type | Pathogenic / likely pathogenic (★) |
| ATM M1L | 1 | Pathogenic / likely pathogenic (★) | |
| BARD1 K438N | 438 | ANK 1 | Pathogenic / likely pathogenic (★) |
| CHEK2 R148S | 148 | FHA | Pathogenic / likely pathogenic (★) |
| ATM R1095I | 1095 | Pathogenic / likely pathogenic (★) | |
| CHEK2 D368H | 368 | Protein kinase | Pathogenic / likely pathogenic (★) |
| PALB2 G562R | 562 | DNA-binding (with the preference D loop > dsDNA | Pathogenic / likely pathogenic (★) |
Uncertain variants prioritized for review in Hereditary breast cancer
| Variant | Position | Protein part | Clinical label | Evidence |
|---|---|---|---|---|
| BARD1 C71G | 71 | RING-type | Uncertain (★★) | +7: C71Y at the same position is pathogenic; seen in 3.4e-06 of gnomAD DNA copies; REVEL 0.954 |
| CHEK2 G167E | 167 | FHA | Conflicting reports (★) | +6: G167R at the same position is pathogenic; REVEL 0.936 |
Which prediction tools work for Hereditary breast cancer
Observed separation of ClinVar pathogenic / likely pathogenic from benign / likely benign variants (AUROC × 100). This benchmark is not a clinical recommendation.
- AlphaMissense: 99 out of 100
- CADD: 95 out of 100
- REVEL: 94 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- phyloP: 93 out of 100
- PolyPhen-2: 91 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- SIFT: 90 out of 100
- MutPred2: 90 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- CATVariant: 84 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- MetaLR: 66 out of 100 (learned from overlapping clinical labels, so this is optimistic)
Same protein, different disease
- Li-Fraumeni syndrome also has ClinVar records linked to TP53 variants; they fall mostly in different places as the Hereditary breast cancer variants (188 pathogenic / likely pathogenic).
- Adrenocortical carcinoma, hereditary also has ClinVar records linked to TP53 variants; they fall mostly in different places as the Hereditary breast cancer variants (23 pathogenic / likely pathogenic).
- Acute myeloid leukemia also has ClinVar records linked to TP53 variants; they fall mostly in different places as the Hereditary breast cancer variants (6 pathogenic / likely pathogenic).
- Glioma susceptibility 1 also has ClinVar records linked to TP53 variants; they fall partly in the same places as the Hereditary breast cancer variants (5 pathogenic / likely pathogenic).
- Hereditary breast ovarian cancer syndrome also has ClinVar records linked to TP53 variants; they fall mostly in different places as the Hereditary breast cancer variants (5 pathogenic / likely pathogenic).
- Ataxia-telangiectasia syndrome also has ClinVar records linked to ATM variants; they fall mostly in different places as the Hereditary breast cancer variants (3 pathogenic / likely pathogenic).
Diseases related to Hereditary breast cancer
- Hereditary breast ovarian cancer syndrome, also linked to ATM, BARD1, BRCA1, BRCA2 and 8 more
- Ovarian cancer, also linked to AKT1, ATM, BARD1, BRCA1 and 7 more
- Gastric cancer, also linked to ATM, BARD1, BRIP1, CHEK2 and 6 more
- Colorectal cancer, also linked to ATM, CHEK2, KRAS, MLH1 and 2 more
- Breast and/or ovarian cancer, also linked to BARD1, BRIP1, CDH1, CHEK2 and 2 more
- Familial pancreatic carcinoma, also linked to ATM, BRCA1, BRCA2, KRAS and 2 more
- Breast-ovarian cancer, familial, susceptibility to, 1, also linked to BRCA1, BRCA2, BRIP1, PALB2 and 1 more
- Ovarian neoplasm, also linked to BRCA1, BRCA2, BRIP1, PIK3CA and 1 more
- Familial prostate cancer, also linked to BRCA2, CHEK2, KRAS, PTEN and 1 more
- Fanconi anemia complementation group J, also linked to BRCA1, BRCA2, BRIP1 and PALB2
- Urinary bladder cancer, also linked to ATM, KRAS, PIK3CA and TP53
- Prostate cancer, also linked to BRCA2, CDH1, CHEK2 and PTEN
Frequently asked questions
Which genes have records linked to Hereditary breast cancer?
This view contains 17 analyzed proteins: PALB2, TP53, CHEK2, ATM, BARD1 and 12 more. Links come from clinical records and association databases. They do not imply that every listed gene is a validated cause, and missing genes may not yet be analyzed.
What do the clinical classifications mean?
Linked records include 23 pathogenic or likely pathogenic variants, 6,066 variants of uncertain significance and 821 with conflicting classifications. Labels summarize source records; multi-condition records may not make a separate assertion for this disease. Check the original record and review status.
Does the evidence score change a VUS classification?
No. 2 VUS or conflicting variants reach the likely-pathogenic points range on the computable criteria available here. This is a research prioritization signal, not a clinical classification. Patient, family and other required evidence may be missing.
Can I download the variant evidence?
Download the CSV for all 7,092 variants in the selected disease scope, including clinical labels, review status, evidence criteria, predictor scores, functional measurements and population frequency where available.
About this data
Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from eligible public CATVariant analyses of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.
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