RECQL – Hereditary Breast Carcinoma

Hereditary breast carcinoma is a cancer predisposition syndrome characterized by early‐onset breast tumors in families without BRCA1/2 mutations. RECQL (HGNC:9948) encodes a RecQ family DNA helicase involved in double‐strand break repair and genomic stability. Mutations in RECQL have been identified in multiple unrelated BRCA‐negative familial breast cancer probands, supporting its role as a susceptibility gene.

Genetic evidence for autosomal dominant inheritance arises from 9 of 448 BRCA‐negative familial breast cancer cases carrying RECQL variants versus 1 of 1,588 controls (P = 9.14×10⁻⁶) (PMID:25945795). Affected individuals presented heterozygous nonsense (e.g., c.516G>A (p.Leu128Ter)), splice (c.395-2A>G), and missense variants. Segregation data are limited, but the variant spectrum includes 3 truncating and 5 helicase‐disrupting missense alleles, including c.644G>A (p.Arg215Gln).

Functional assays demonstrate that missense variants in RECQL significantly impair in vitro helicase activity, confirming a loss‐of‐function mechanism consistent with cancer risk (PMID:25945795). Helicase‐deficient RECQL proteins show reduced ATPase and DNA‐unwinding capacity, mirroring genomic instability phenotypes.

Case–control analysis provides strong statistical support: 9 probands with RECQL mutations versus 1 control (PMID:25945795). The absence of segregation data in multiple pedigrees limits advanced scoring, but the combination of multiple unrelated probands and concordant functional impairment underscores pathogenicity.

Conflicting evidence arises from a large Spanish cohort study of ~2,000 BRCAX families, which did not observe significant enrichment of RECQL LoF variants, attributing breast cancer risk instead to RECQL5 (PMID:36230663). This suggests possible population specificity or allele heterogeneity.

Integration of genetic and experimental data yields a coherent model: heterozygous RECQL loss‐of‐function impairs DNA repair, leading to genomic instability and increased breast cancer risk. While further segregation and diverse‐population replication are needed, current evidence supports clinical testing of RECQL in familial breast cancer panels.

Key Take‐home: Germline RECQL variants confer a moderate‐to‐high risk of hereditary breast carcinoma via helicase loss of function, meriting inclusion in diagnostic genetic screens.

References

• PLoS genetics • 2015 • Mutations in RECQL Gene Are Associated with Predisposition to Breast Cancer PMID:25945795
• Cancers • 2022 • A Large Case-Control Study Performed in Spanish Population Suggests That RECQL5 Is the Only RECQ Helicase Involved in Breast Cancer Susceptibility PMID:36230663

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