BRCA1 – Fanconi Anemia Type S

BRCA1, a canonical breast and ovarian cancer susceptibility gene, has been newly classified as FANCS, underlying a distinct subtype of Fanconi anemia (FA-S). Fanconi anemia is an autosomal recessive chromosomal instability syndrome characterized by congenital anomalies, bone marrow failure, and cancer predisposition (Fanconi anemia; BRCA1).

1. Clinical Validity Assessment

Multiple unrelated individuals with biallelic BRCA1 mutations demonstrated FA-like features without classic bone marrow failure. Four probands exhibited short stature, microcephaly, developmental delay, congenital anomalies, and hypersensitivity to DNA crosslinking agents (1 proband, c.2457delC; [PMID:23269703]), (1 proband, c.5096G>T; [PMID:25472942]), (1 proband, c.2709T>A; [PMID:29133208]), (1 proband, c.181T>G/c.5096G>A; [PMID:31347298]). Accordingly, the gene–disease association is classified as Moderate.

2. Genetic Evidence

Inheritance is autosomal recessive. Four unrelated probands harbored compound heterozygous or homozygous BRCA1 variants including frameshift and missense alleles: c.5207T>C (p.Val1736Ala) and c.2457delC (p.Asp821IlefsTer25) among others. No extended segregation of FA phenotype was reported; cancer cosegregation was noted for p.Val1736Ala in families predisposed to breast/ovarian cancer ([PMID:23269703]). Variant spectrum includes 2 truncating and 2 hypomorphic missense alleles.

3. Functional Evidence

Cellular assays demonstrate that FA-S–associated BRCA1 missense variants impair DNA damage response: p.Val1736Ala reduces BRCA1 focus formation and chromosomal stability ([PMID:23269703]); p.Arg1699Leu/Arg1699Gln compromises RAD51 recruitment and replication stress protection, rescued by BRCA1 transgene expression ([PMID:25472942], [PMID:31347298]). Homozygous truncating variants elevate chromosomal breakage and DEB sensitivity ([PMID:29133208]). These data support a loss-of-function mechanism consistent with FA pathogenesis.

4. Conflicting Evidence

A male dual carrier of two BRCA1 variants (c.2475del and exon20dup) exhibited no FA phenotype, indicating that residual BRCA1 activity above a critical threshold may prevent FA-S despite biallelic mutation ([PMID:38195559]).

5. Integrated Conclusion

Biallelic BRCA1 mutations cause a distinct FA-S phenotype via loss of homologous recombination and interstrand crosslink repair. Genetic evidence from four AR cases, complemented by concordant functional assays, supports a Moderate level of clinical validity. Further genotype–phenotype correlations and segregation studies are needed to reach a Strong classification.

Key Take-home: Testing for biallelic BRCA1 variants should be considered in FA-like presentations without bone marrow failure to guide genetic counseling and targeted management.

References

• Cancer discovery • 2013 • Biallelic deleterious BRCA1 mutations in a woman with early-onset ovarian cancer. PMID:23269703
• Cancer discovery • 2015 • Biallelic mutations in BRCA1 cause a new Fanconi anemia subtype. PMID:25472942
• European journal of medical genetics • 2018 • Homozygous loss of function BRCA1 variant causing a Fanconi-anemia-like phenotype, a clinical report and review of previous patients. PMID:29133208
• Molecular genetics & genomic medicine • 2019 • Biallelic germline BRCA1 mutations in a patient with early onset breast cancer, mild Fanconi anemia-like phenotype, and no chromosome fragility. PMID:31347298

Evidence Based Scoring (AI generated)