FANCC – Ovarian Cancer Predisposition

Heterozygous germline pathogenic variants in FANCC have been identified in multiple ovarian cancer cohorts, although gene-specific counts remain low. In a large series of 882 unselected ovarian cancer patients, 56 (6.3%) carried pathogenic variants in non-BRCA homologous recombination genes, including FANCC (PMID:38041901). Among Ashkenazi Jewish patients, 2.7% of pathogenic non-BRCA1/2 mutations involved non-BRCA cancer-associated genes such as FANCC (PMID:30480775). In a Chinese familial breast and ovarian cancer cohort (n=255), one proband harbored FANCC c.339G>A (p.Trp113Ter) (PMID:30967997). No familial segregation data have been reported for ovarian cancer.

FANCC encodes a core component of the Fanconi anemia DNA repair pathway. Monoallelic loss leads to homologous recombination deficiency and increased tumor mutational burden in ovarian tumors, analogous to other HR genes (PMID:38041901). Functional assays in FA-C patient cells demonstrate impaired interstrand crosslink repair and cytokine signaling defects, supporting a haploinsufficiency mechanism (PMID:8639804).

Clinical guidelines classify FANCC as a moderate-risk ovarian cancer gene (10–20% lifetime risk) and recommend inclusion in multigene testing panels and consideration of prophylactic salpingo-oophorectomy for carriers with significant family history (PMID:31409076). Further case series and segregation studies are required to refine risk estimates.

Key Take-home: FANCC pathogenic variants confer moderate ovarian cancer risk and warrant inclusion in hereditary cancer panels under current clinical guidelines.

References

• Gynecologic oncology • 2024 • Pathogenic germline variants in non-BRCA1/2 homologous recombination genes in ovarian cancer PMID:38041901
• Klinicka onkologie : casopis Ceske a Slovenske onkologicke spolecnosti • 2019 • Recommendations for Preventive Care for Women with Rare Genetic Cause of Breast and Ovarian Cancer PMID:31409076
• Frontiers in oncology • 2019 • Deleterious Mutations in DNA Repair Gene FANCC Exist in BRCA1/2-Negative Chinese Familial Breast and/or Ovarian Cancer Patients PMID:30967997
• Blood • 1996 • Clinical variability of Fanconi anemia (type C) results from expression of an amino terminal truncated Fanconi anemia complementation group C polypeptide with partial activity PMID:8639804
• Cancer • 2019 • Prevalence of nonfounder BRCA1/2 mutations in Ashkenazi Jewish patients presenting for genetic testing at a hereditary breast and ovarian cancer center PMID:30480775

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