Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong
The NM_002576.5(PAK1):c.1117-3T>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,409,276 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).
PAK1 (HGNC:8590): (p21 (RAC1) activated kinase 1) This gene encodes a family member of serine/threonine p21-activating kinases, known as PAK proteins. These proteins are critical effectors that link RhoGTPases to cytoskeleton reorganization and nuclear signaling, and they serve as targets for the small GTP binding proteins Cdc42 and Rac. This specific family member regulates cell motility and morphology. Mutations in this gene have been associated with macrocephaly, seizures, and speech delay. Overexpression of this gene is also reported in many cancer types, and particularly in breast cancer. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2020]
Uncertain significance, criteria provided, single submitter
clinical testing
Ambry Genetics
Jul 05, 2022
The c.1117-3T>C intronic alteration consists of a T to C substitution 3 nucleotides before coding exon 11 in the PAK1 gene. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -