Germline heterozygous SH2B3 p.Glu78Lys variant: a three-patient case series with myeloproliferative neoplasms

Abstract

We investigated the clinical significance of a rare germline SH2B3 variant (c.232G>A; p.Glu78Lys) identified by targeted next-generation sequencing (NGS) in patients with myeloproliferative neoplasms (MPNs). Among approximately 330 patients, three heterozygous carriers (≈1.0% prevalence) were identified by NGS and confirmed as germline (buccal swab) by Sanger sequencing. Two of the carriers presented with essential thrombocythemia that progressed to secondary myelofibrosis, and one presented with primary myelofibrosis that evolved to acute myeloid leukemia. The variant co-occurred with canonical somatic drivers (CALR or MPL) in the first two cases and with MPL plus additional somatic alterations (SRSF2, TET2) in the third. The p.Glu78Lys substitution localizes in the N-terminal dimerization domain of SH2B3. This germline variant is rare in population databases (allele frequency ∼1.1–2.2 per 1,000 inhabitants), and is currently classified as a variant of uncertain significance. In silico predictions were discordant, whereas structural modeling predicts disruption of critical hydrogen bonding at the dimer interface, suggesting potential functional impact. Although heterozygosity alone appears insufficient to drive disease, the enrichment of this variant in our MPN cohort and its occurrence in relatively young patients support a possible low-penetrance predisposition role. Functional assays, larger case–control series, and assessment of genetic/epigenetic modifiers are needed to define pathogenicity and clinical utility.