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Autosomal dominant inheritance is suggested for RASAL1-associated breast cancer predisposition. Whole exome sequencing in two first-degree cousin pairs identified rare damaging RASAL1 variants in four probands (PMID:32906649). Targeted analysis of 131 BRCA1/2-negative patients uncovered additional novel and rare RASAL1 alleles with a significant case enrichment (PMID:32906649). No extended segregation beyond index cases was reported.
Functional transcript analysis demonstrated that RASAL1 splice site alterations impair correct mRNA formation, consistent with a loss-of-function mechanism (PMID:32906649). These in vitro RNA studies provide preliminary evidence but lack in vivo modeling or rescue experiments. Further replication in larger cohorts and functional validation are required to confirm RASAL1 as a breast cancer susceptibility gene.
Key take-home: Preliminary genetic and transcriptomic data link RASAL1 loss-of-function variants to hereditary breast cancer risk, warranting additional familial and experimental studies for clinical translation.
Gene–Disease AssociationLimitedVariants identified in two cousin pairs (4 probands) and nominal enrichment in 131 BRCA1/2-negative patients (PMID:32906649) Genetic EvidenceLimited4 probands across two families and rare variant enrichment in targeted cohort (PMID:32906649) Functional EvidenceLimitedIn vitro assays show splice site variants impair transcript formation without in vivo validation (PMID:32906649) |