Phenotypic manifestations and variant reclassification of germline <i>PTEN</i> variants: a nationwide Danish study.

Abstract

Classification of heterozygous germline <i>PTEN</i> variants in patients with, or suspected of having, <i>PTEN</i> hamartoma tumour syndrome (PHTS) remains challenging. Accurate classification is essential as these patients require lifelong cancer surveillance. We identified all patients with a <i>PTEN</i> variant previously classified as a variant of uncertain significance (VUS), likely pathogenic (LP) or pathogenic (P), collected clinical data and reclassified all variants using the latest <i>PTEN</i> gene-specific American College of Medical Genetics (ACMG) guidelines. Moreover, genotype-phenotype correlations were assessed. 167 patients from 112 families were enrolled. Eighty-seven unique <i>PTEN</i> variants were identified, including 20 novel variants. After applying the <i>PTEN</i> gene<i>-</i>specific ACMG guidelines, 32 variants (36.8%) were reclassified, resulting in 60 <i>PTEN</i> variants classified as LP/P (69.0%), 18 variants classified as VUS (20.7%), while 9 variants were classified as LB/B (10.3%). Genotype-phenotype correlation was performed among 104 patients with LP/P variants: 51 cancer cases were recorded in 41 patients and a distinct PHTS phenotype was observed in 25% of patients, with macrocephaly being present in 99% of patients with a known head circumference. Twenty-three patients had neurodevelopmental delay and/or autism, and we observed an increased prevalence of missense variants in these patients. We identified 87 different <i>PTEN</i> variants, and application of <i>PTEN</i> gene-specific ACMG guidelines led to reclassification of 32 variants (36.8%), underscoring the importance of regular variant reassessment using the most recent gene-specific guidelines, ensuring optimal patient management and surveillance.