ClinVar Genomic variation as it relates to human health

PTEN c.1026+1G>A (IVS8+1G>A) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (Mester et al. 2018; manuscript in preparation). Please see a summary of the rules and criteria codes in the 'PTEN ACMG Specifications Summary' document (assertion method column). PVS1: Null variant predicted to result in nonsense-mediated decay or causing truncation/frameshift at or 5' to c.1121 (NM_000314.4) (PMID 28677221). PM2: Absent in large sequenced populations (PMID 27535533). PS4_M: Probands with phenotype specificity score of 2-3.5. (PMID 28677221, internal laboratory contributor(s) SCV000212764.4)

For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant is associated with altered splicing, but the impact on the resulting protein product is unknown (PMID: 28677221; Invitae). ClinVar contains an entry for this variant (Variation ID: 183722). This variant is also known as IVS8+1G>A. Disruption of this splice site has been observed in individuals with Cowden or Cowden-like syndrome (PMID: 21194675, 28677221). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 8 of the PTEN gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product.

Canonical splice site variant demonstrated to result in an abnormal protein product, disrupting the critical C2 domain (PMID: 18626510, 28677221); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 15372512, 21194675, 28677221, 30311380, 18626510, 36131570, 34386506, 29891884, 31263500, 35931053, 36746884)

This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function.

The c.1026+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 8 of the PTEN gene. In one study, RNA analysis showed that this variant led to abnormal splicing with retention of 190 nt from intron 8 and introduction of a stop codon at p.345 that would result in loss of amino acids encompassing exon 9 (Chen HJ et al. Hum Mutat, 2017 10;38:1372-1377). This alteration has been reported in multiple individuals meeting clinical criteria for Cowden syndrome (Agrawal S et al. Hum Mol Genet. 2005 Aug;14(16):2459-68; Tan MH et al. Am. J. Hum. Genet. 2011 Jan; 88(1):42-56; Chen HJ et al. Hum Mutat, 2017 10;38:1372-1377; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.