FANCC – Breast Cancer Susceptibility

Heterozygous truncating variants in FANCC have been observed in familial breast cancer cases, initially identified by exome sequencing of 33 individuals from 15 high-risk families, yielding 3 families with such variants absent in controls (PMID:23028338). A subsequent hotspot screen added one more FANCC truncation in an additional 957 families (PMID:23028338). In a Chinese FBOC cohort, one truncating mutation c.339G>A (p.Trp113Ter) was found in 255 BRCA1/2-negative patients and absent in 248 controls (PMID:30967997). Population-based analysis in African American women showed a moderate enrichment of FANCC mutations in ER-positive breast cancer versus controls, supporting a moderate risk association (PMID:32427313). However, a large Oncoarray study of 64,760 European descent cases and 49,793 controls detected FANCC truncating variants in similar frequencies among cases and controls (25 cases vs 26 controls; OR 0.77, p=0.4) (PMID:31467304). Ashkenazi Jewish multigene panel testing found FANCC among non-BRCA genes in 2.7% of patients, indicating low-to-moderate risk alleles (PMID:30480775). In silico analyses of Tunisian breast cancer families suggest potential functional destabilization of FANCC variants but lack segregation data (PMID:38313678). Collectively, these data support a limited and heterogeneous association between monoallelic FANCC variants and breast cancer susceptibility.

References

• PLoS genetics • 2012 • Exome sequencing identifies rare deleterious mutations in DNA repair genes FANCC and BLM as potential breast cancer susceptibility alleles. PMID:23028338
• Scientific reports • 2019 • Two truncating variants in FANCC and breast cancer risk. PMID:31467304
• Journal of the National Cancer Institute • 2020 • Contribution of Germline Predisposition Gene Mutations to Breast Cancer Risk in African American Women. PMID:32427313
• 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
• 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
• Frontiers in genetics • 2024 • Uncovering the clinical relevance of unclassified variants in DNA repair genes: a focus on BRCA negative Tunisian cancer families. PMID:38313678

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