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SLX4 – Hereditary Breast Carcinoma

Whole exome sequencing of 45 Lebanese familial breast cancer patients identified four SLX4 coding variants, including one nonsense c.2469G>A (p.Trp823Ter) and three rare missense alleles, together accounting for ~2% of cases, with no clear pathogenic variants replicated in a Spanish cohort of 94 BRCA1/2-negative families (PMID:28202063; PMID:22401137). The paucity of recurrent or segregating variants and absence of multi-family segregation data limit the genetic association.

Functional complementation studies in human SLX4-null fibroblasts demonstrate that the nonsense p.Trp823Ter mutant fails to rescue sensitivity to mitomycin C, camptothecin, and PARP inhibitors, consistent with a loss-of-function mechanism (PMID:23840564). Furthermore, the interaction-defective SLX4(Y546C) allele cannot bind XPF and does not complement interstrand cross-link repair in murine cell models (PMID:26453996). Despite these concordant functional data, the clinical evidence remains limited for SLX4 in hereditary breast carcinoma.

References

  • BMC medical genomics • 2017 • Next-generation sequencing in familial breast cancer patients from Lebanon. PMID:28202063
  • BMC cancer • 2012 • Analysis of SLX4/FANCP in non-BRCA1/2-mutated breast cancer families. PMID:22401137
  • PloS one • 2013 • Assessment of SLX4 Mutations in Hereditary Breast Cancers. PMID:23840564
  • DNA repair • 2015 • Physical interaction between SLX4 (FANCP) and XPF (FANCQ) proteins and biological consequences of interaction-defective missense mutations. PMID:26453996

Evidence Based Scoring (AI generated)

Gene–Disease Association

Limited

One nonsense variant in a single proband and rare missense alleles observed without replication or segregation in multiple families (PMID:23840564; PMID:28202063; PMID:22401137)

Genetic Evidence

Limited

Single proband with LoF c.2469G>A (p.Trp823Ter) and absence of confirmed pathogenic variants in larger cohorts (PMID:23840564; PMID:22401137; PMID:28202063)

Functional Evidence

Moderate

Loss-of-function of p.Trp823Ter in cellular rescue assays and disruption of XPF interaction by Y546C demonstrate coherent mechanistic impact (PMID:23840564; PMID:26453996)