Breast-ovarian cancer, familial, susceptibility to, 1: genes and variants

Genes linked to Breast-ovarian cancer, familial, susceptibility to, 1

• RAD51C: DNA repair protein RAD51 homolog 3

  It participates in RAD51-paralog complexes that promote homologous-recombination repair and restart damaged replication forks. Heterozygous loss-of-function variants increase ovarian and breast-cancer risk, while biallelic variants can cause Fanconi anemia.

  9 disease-causing and 198 uncertain variants in RAD51C are linked to Breast-ovarian cancer, familial, susceptibility to, 1.

• 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.

  1 disease-causing and 79 uncertain variants in PALB2 are linked to Breast-ovarian cancer, familial, susceptibility to, 1.

• MSH2: DNA mismatch repair protein Msh2

  The protein forms mismatch-recognition complexes with MSH6 or MSH3 that detect base mismatches and insertion-deletion loops in DNA. This first step of mismatch repair helps preserve genome integrity, and inherited MSH2 variants are associated with Lynch syndrome.

  1 disease-causing and 1 uncertain variants in MSH2 are linked to Breast-ovarian cancer, familial, susceptibility to, 1.

• ATP7B: Copper-transporting ATPase 2

  A copper-transporting ATPase that moves excess copper out of cells and helps deliver it from liver cells into bile. Its trafficking between intracellular membranes is central to copper homeostasis, and ATP7B dysfunction causes Wilson disease.

  1 disease-causing and 0 uncertain variants in ATP7B are linked to Breast-ovarian cancer, familial, susceptibility to, 1.

• STK11: Serine/threonine-protein kinase STK11

  It activates AMPK-family kinases to coordinate cellular energy sensing, polarity, and growth restraint. Germline loss-of-function variants cause Peutz-Jeghers syndrome and its associated cancer predisposition, while somatic loss is common in lung and other cancers.

  1 disease-causing and 0 uncertain variants in STK11 are linked to Breast-ovarian cancer, familial, susceptibility to, 1.

• 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.

  1 disease-causing and 0 uncertain variants in TP53 are linked to Breast-ovarian cancer, familial, susceptibility to, 1.

• 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.

  0 disease-causing and 3 uncertain variants in BRIP1 are linked to Breast-ovarian cancer, familial, susceptibility to, 1.

• 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 disease-causing and 1 uncertain variants in BRCA2 are linked to Breast-ovarian cancer, familial, susceptibility to, 1.

• 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 disease-causing and 0 uncertain variants in BRCA1 are linked to Breast-ovarian cancer, familial, susceptibility to, 1.

• RAD51D: DNA repair protein RAD51 homolog 4

  It supports RAD51-mediated homologous recombination and chromosome stability after DNA double-strand breaks. Heterozygous loss-of-function variants confer substantial ovarian-cancer risk and a more moderate increase in breast-cancer susceptibility.

  0 disease-causing and 595 uncertain variants in RAD51D are linked to Breast-ovarian cancer, familial, susceptibility to, 1.

Weakly linked (only a few uncertain records): RAD50, CHEK2, MLH1, MSH6 and NBN.

Where Breast-ovarian cancer, familial, susceptibility to, 1 variants cluster

• RAD51C Interaction with RAD51B, RAD51D and XRCC3 (positions 79–136): 6 of 9 disease-causing changes, 4.3× more than its size predicts.

Known disease-causing variants in Breast-ovarian cancer, familial, susceptibility to, 1

Uncertain variants in Breast-ovarian cancer, familial, susceptibility to, 1 that look disease-causing

Which prediction tools work for Breast-ovarian cancer, familial, susceptibility to, 1

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

• PolyPhen-2: 93 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 84 out of 100
• CATVariant: 74 out of 100 (learned from overlapping clinical labels, so this is optimistic)

Same protein, different disease

• Lynch syndrome is also caused by MSH2 variants; they fall mostly in different places as the Breast-ovarian cancer, familial, susceptibility to, 1 variants (22 disease-causing).
• Hereditary nonpolyposis colorectal neoplasms is also caused by MSH2 variants; they fall mostly in different places as the Breast-ovarian cancer, familial, susceptibility to, 1 variants (12 disease-causing).
• Li-Fraumeni syndrome is also caused by TP53 variants; they fall mostly in different places as the Breast-ovarian cancer, familial, susceptibility to, 1 variants (188 disease-causing).
• Adrenocortical carcinoma, hereditary is also caused by TP53 variants; they fall mostly in different places as the Breast-ovarian cancer, familial, susceptibility to, 1 variants (23 disease-causing).
• Acute myeloid leukemia is also caused by TP53 variants; they fall mostly in different places as the Breast-ovarian cancer, familial, susceptibility to, 1 variants (6 disease-causing).
• Familial cancer of breast is also caused by TP53 variants; they fall mostly in different places as the Breast-ovarian cancer, familial, susceptibility to, 1 variants (5 disease-causing).
• Glioma susceptibility 1 is also caused by TP53 variants; they fall mostly in different places as the Breast-ovarian cancer, familial, susceptibility to, 1 variants (5 disease-causing).
• Wilson disease is also caused by ATP7B variants; they fall mostly in different places as the Breast-ovarian cancer, familial, susceptibility to, 1 variants (222 disease-causing).
• Peutz-Jeghers syndrome is also caused by STK11 variants; they fall mostly in different places as the Breast-ovarian cancer, familial, susceptibility to, 1 variants (24 disease-causing).
• Melanoma, cutaneous malignant, susceptibility to, 8 is also caused by STK11 variants; they fall mostly in different places as the Breast-ovarian cancer, familial, susceptibility to, 1 variants (4 disease-causing).

Diseases related to Breast-ovarian cancer, familial, susceptibility to, 1

• Hereditary breast ovarian cancer syndrome, also linked to BRCA1, BRCA2, BRIP1, PALB2 and 3 more
• Ovarian cancer, also linked to BRCA1, BRCA2, BRIP1, MSH2 and 2 more
• Breast and/or ovarian cancer, also linked to BRIP1, MSH2, RAD51C, RAD51D and 2 more
• Gastric cancer, also linked to BRIP1, PALB2, RAD51C, RAD51D and 1 more
• Familial pancreatic carcinoma, also linked to BRCA1, BRCA2, PALB2, STK11 and 1 more
• Fanconi anemia, also linked to BRCA2, BRIP1, PALB2 and RAD51C
• Ovarian neoplasm, also linked to BRCA1, BRCA2, BRIP1 and TP53
• Familial cancer of breast, also linked to BRIP1, PALB2 and TP53
• Familial ovarian cancer, also linked to BRIP1, RAD51C and RAD51D
• Acute myeloid leukemia, also linked to PALB2 and TP53
• Colorectal cancer, also linked to MSH2 and TP53
• Glioma susceptibility 1, also linked to BRCA2 and TP53

Frequently asked questions

Which genes are linked to Breast-ovarian cancer, familial, susceptibility to, 1?

In CATVariant, Breast-ovarian cancer, familial, susceptibility to, 1 is linked to 10 analyzed proteins: RAD51C (DNA repair protein RAD51 homolog 3), PALB2 (Partner and localizer of BRCA2), MSH2 (DNA mismatch repair protein Msh2), ATP7B (Copper-transporting ATPase 2), STK11 (Serine/threonine-protein kinase STK11), TP53 (Cellular tumor antigen p53) and 4 more.

How many genetic variants are linked to Breast-ovarian cancer, familial, susceptibility to, 1?

904 variants: 14 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 884 are of uncertain significance or have conflicting reports.

Which uncertain variants in Breast-ovarian cancer, familial, susceptibility to, 1 look disease-causing?

4 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example RAD51C K131I, RAD51C G125S, RAD51C K131Q and RAD51C C135W. These are leads for expert review, not diagnoses.

Which variant effect predictor works best for Breast-ovarian cancer, familial, susceptibility to, 1?

Among tools not trained on clinical labels, SIFT separates this disease's known disease-causing variants from harmless ones best (AUROC 0.84, based on 9 disease-causing and 628 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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