PTEN NM_000314.8:c.253+5G>A, ?

The c.253+5G>A intronic variant results from a G to A substitution 5 nucleotides after coding exon 4 in the PTEN gene. This alteration was identified in an individual with macrocephaly, thyroid lesions and genitourinary tumors. RNA studies were performed for this variant and was associated with CDS 4 skipping (Chen HJ et al. Hum Mutat, 2017 Oct;38:1372-1377, Ambry internal data). Additionally, this variant has been observed in at least one individual with a personal and/or family history that is consistent with PTEN hamartoma tumor syndrome (External communication). Another alteration impacting the same donor site (c.253+5G>T) has been shown to have a similar impact on splicing in an individual with PTEN hamartoma tumor syndrome (Vanderver A et al. Am J Med Genet A, 2014 Mar;164A:627-33, Ambry internal data). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration (c.253+5G>A) will weaken the native splice donor site. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.

This sequence change falls in intron 4 of the PTEN gene. It does not directly change the encoded amino acid sequence of the PTEN protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or altered protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with Cowden syndrome (PMID: 28677221). ClinVar contains an entry for this variant (Variation ID: 427618). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 4, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 28677221). This variant disrupts the c.253+5G nucleotide in the PTEN gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 24375884, 28677221; internal data). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.