Familial cancer of breast: genes and variants

Genes linked to Familial cancer of breast

• 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 disease-causing and 1,846 uncertain variants in PALB2 are linked to Familial cancer of breast.

• 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 disease-causing and 21 uncertain variants in TP53 are linked to Familial cancer of breast.

• 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 disease-causing and 1,371 uncertain variants in CHEK2 are linked to Familial cancer of breast.

• 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 disease-causing and 95 uncertain variants in ATM are linked to Familial cancer of breast.

• 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 disease-causing and 1,507 uncertain variants in BARD1 are linked to Familial cancer of breast.

• 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 disease-causing and 1,835 uncertain variants in BRIP1 are linked to Familial cancer of breast.

• 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 disease-causing and 4 uncertain variants in PIK3CA are linked to Familial cancer of breast.

• 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 disease-causing and 1 uncertain variants in KRAS are linked to Familial cancer of breast.

• 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 disease-causing and 0 uncertain variants in EPCAM are linked to Familial cancer of breast.

• 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 disease-causing and 0 uncertain variants in PTEN are linked to Familial cancer of breast.

• 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 disease-causing and 169 uncertain variants in CDH1 are linked to Familial cancer of breast.

• 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 disease-causing and 16 uncertain variants in RAD50 are linked to Familial cancer of breast.

• 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 disease-causing and 7 uncertain variants in AKT1 are linked to Familial cancer of breast.

Weakly linked (only a few uncertain records): ESR1, ERBB2, PPM1D, ABCC1, BRCA1, BRCA2, CASP8, FANCD2 and 6 more.

Where Familial cancer of breast variants cluster

• PALB2 Required for its oligomerization and is importan (positions 1–160): 4 of 5 disease-causing changes, 5.9× more than its size predicts.
• TP53 Interaction with AXIN1 (positions 116–292): 5 of 5 disease-causing changes, 2.2× more than its size predicts.

Known disease-causing variants in Familial cancer of breast

Uncertain variants in Familial cancer of breast that look disease-causing

Which prediction tools work for Familial cancer of breast

How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).

• AlphaMissense: 99 out of 100
• CADD: 95 out of 100
• REVEL: 95 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 is also caused by TP53 variants; they fall mostly in different places as the Familial cancer of breast variants (188 disease-causing).
• Adrenocortical carcinoma, hereditary is also caused by TP53 variants; they fall mostly in different places as the Familial cancer of breast variants (23 disease-causing).
• Acute myeloid leukemia is also caused by TP53 variants; they fall mostly in different places as the Familial cancer of breast variants (6 disease-causing).
• Glioma susceptibility 1 is also caused by TP53 variants; they fall partly in the same places as the Familial cancer of breast variants (5 disease-causing).
• Hereditary breast ovarian cancer syndrome is also caused by TP53 variants; they fall mostly in different places as the Familial cancer of breast variants (5 disease-causing).
• Ataxia-telangiectasia syndrome is also caused by ATM variants; they fall mostly in different places as the Familial cancer of breast variants (3 disease-causing).

Diseases related to Familial cancer of breast

• Gastric cancer, also linked to ATM, BARD1, BRIP1, CHEK2 and 5 more
• Hereditary breast ovarian cancer syndrome, also linked to ATM, BARD1, BRIP1, CDH1 and 5 more
• Ovarian cancer, also linked to AKT1, ATM, BARD1, BRIP1 and 3 more
• Colorectal cancer, also linked to ATM, CHEK2, KRAS, PIK3CA and 1 more
• Breast and/or ovarian cancer, also linked to BARD1, BRIP1, CDH1, CHEK2 and 1 more
• Familial pancreatic carcinoma, also linked to ATM, KRAS, PALB2 and TP53
• Cowden syndrome, also linked to AKT1, PIK3CA and PTEN
• Acute myeloid leukemia, also linked to KRAS, PALB2 and TP53
• Breast-ovarian cancer, familial, susceptibility to, 1, also linked to BRIP1, PALB2 and TP53
• Ovarian neoplasm, also linked to BRIP1, PIK3CA and TP53
• Prostate cancer, also linked to CDH1, CHEK2 and PTEN
• Endometrial carcinoma, also linked to CDH1, PIK3CA and PTEN

Frequently asked questions

Which genes are linked to Familial cancer of breast?

In CATVariant, Familial cancer of breast is linked to 13 analyzed proteins: PALB2 (Partner and localizer of BRCA2), TP53 (Cellular tumor antigen p53), CHEK2 (Serine/threonine-protein kinase Chk2), ATM (Serine-protein kinase ATM), BARD1 (BRCA1-associated RING domain protein 1), BRIP1 (Fanconi anemia group J protein) and 7 more.

How many genetic variants are linked to Familial cancer of breast?

6,926 variants: 23 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 6,887 are of uncertain significance or have conflicting reports.

Which uncertain variants in Familial cancer of breast look disease-causing?

2 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example BARD1 C71G and CHEK2 G167E. These are leads for expert review, not diagnoses.

Which variant effect predictor works best for Familial cancer of breast?

Among tools not trained on clinical labels, AlphaMissense separates this disease's known disease-causing variants from harmless ones best (AUROC 0.99, based on 8 disease-causing and 335 harmless variants).

About this data

Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis 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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