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BRIP1 – Hereditary Breast Carcinoma

BRIP1 has been evaluated as a candidate moderate-penetrance gene for autosomal dominant hereditary breast carcinoma. Two rare heterozygous variants have been reported in index patients: a truncating frameshift c.2992_2995del (p.Lys998fsTer) causing BRCA1-binding disruption and protein instability with loss of the wild-type allele in tumor tissue (PMID:18628483), and a missense c.550G>T (p.Asp184Tyr) that creates a novel splice enhancer leading to exon 5 skipping and predicted helicase domain loss (PMID:30230034). No extended family segregation has been documented.

However, large-scale analyses have not supported a substantial role for BRIP1 in breast cancer predisposition. In 111 Finnish families, multiplex ligation-dependent probe amplification found no exonic rearrangements in BRIP1 (PMID:20567916), and German case-control studies of Pro919Ser and –64G>A variants showed no significant risk differences (PMID:17504528).

References

  • Molecular Carcinogenesis • 2019 • Unraveling the molecular effect of a rare missense mutation in BRIP1 associated with inherited breast cancer. PMID:30230034
  • Clinical Cancer Research • 2008 • A novel breast cancer-associated BRIP1 (FANCJ/BACH1) germ-line mutation impairs protein stability and function. PMID:18628483
  • Familial Cancer • 2010 • Screening for large genomic rearrangements of the BRIP1 and CHK1 genes in Finnish breast cancer families. PMID:20567916
  • BMC Cancer • 2007 • BRIP1 (BACH1) variants and familial breast cancer risk: a case-control study. PMID:17504528

Evidence Based Scoring (AI generated)

Gene–Disease Association

Limited

Single-family reports of two pathogenic BRIP1 variants with no segregation ([PMID:30230034], [PMID:18628483]) contrasted by negative large familial and case-control studies ([PMID:20567916], [PMID:17504528]).

Genetic Evidence

Limited

Two probands with rare BRIP1 variants, no extended segregation data, total of two variant classes observed.

Functional Evidence

Moderate

Splicing assay demonstrates exon 5 skipping for c.550G>T ([PMID:30230034]); truncation c.2992_2995del disrupts BRCA1 binding and protein stability in cell models ([PMID:18628483]).