Phenotypic manifestations and variant reclassification of germline PTEN variants: a nationwide Danish study.

PTEN

Heterozygous germline PTEN variants, reclassified using the gene-specific ACMG criteria

This nationwide Danish study gathered every patient carrying a PTEN variant previously classified as a variant of uncertain significance, likely pathogenic or pathogenic: 167 patients from 112 families and 87 unique variants, including 20 novel ones. Applying the PTEN gene-specific ACMG criteria reclassified 32 variants (36.8%): 60 variants ended up likely pathogenic or pathogenic (69.0%), 18 remained of uncertain significance (20.7%) and 9 became benign or likely benign (10.3%). Genotype-phenotype correlation in the 104 patients with likely pathogenic or pathogenic variants recorded 51 cancers in 41 patients and a distinct phenotype in 25% of them, with macrocephaly present in 99% of patients whose head circumference was known. Twenty-three patients had developmental delay and/or autism, with an increased prevalence of missense variants in this subgroup.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

A third of variants reclassified in a nationwide series is the figure to remember: it quantifies the cost of not reassessing, for a gene whose diagnosis commits patients to lifelong cancer surveillance. The nine variants downgraded to benign represent as many families potentially released from a demanding protocol, which is clinically as important as upgrades toward pathogenicity. The limitation is ascertainment: the series starts from patients already tested and retained, so the 25% rate of distinct phenotype and the 51 cancers reflect a genetics-referred population, not penetrance in the general population.

Analysis by Dr Thibaut Benquey