Thrombocythaemia

Gene: SH2B3

Green List (high evidence)

PMID: 41325922 Iaquinta et al 2025 - report of 3 individuals with the same germline heterozygous SH2B3 c.232G>A, p.Glu78Lys variant. They screened 330 patients with myeloproliferative neoplasms with a 73 gene panel. 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 (AML). 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. Distant familial relatedness was not explored. The variant is rare in gnomAD v4.1.0 with a frequency of 0.001097. The authors conclude that heterozygosity alone appears insufficient to drive disease, but supports a low-penetrance predisposition role.

PMID: 40481232 Leardini et al 2025 - 10 children from 9 families with SH2B3-associated neonatal myeloproliferative disease, arising from germline biallelic SH2B3 loss-of-function (LoF) mutations in 8 and in 2 patients with monoallelic germline LoF variants with loss-of-heterozygosity in hematopoietic cells. 9 different variants reported. This was a international, multicenter, retrospective study on paediatric patients with germline variants in SH2B3. Two patients were previously reported in PMID: 38152053. Patients ranged in age from 0–4.0 years. The VAF in blood for patient P8.1 who carries a germline monoallelic variant, was close to 100%, suggesting a near-complete replacement of normal hematopoiesis by the mutant clone. Note: additional somatic driver mutations in other genes were not looked for. Some heterozygous unaffected parents reported. Heterozygous mother of one homozgyous proband is reported to have had Thrombocytosis from adolescence.

Created: 11 Dec 2025, 11:21 p.m. | Last Modified: 11 Dec 2025, 11:35 p.m.

Panel Version: 1.11

Comment on phenotypes: Phenotype accessed in OMIM on 11th Dec 2025

Created: 11 Dec 2025, 5:44 p.m. | Last Modified: 11 Dec 2025, 5:44 p.m.

Panel Version: 1.10

Comment on publications: Adding the PubMed ID of 40481232 for Leardini et al 2025

Created: 11 Dec 2025, 5:33 p.m. | Last Modified: 11 Dec 2025, 5:33 p.m.

Panel Version: 1.9

The rating of this gene has been updated to green and the mode of inheritance updated to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.

Created: 11 Dec 2025, 5:30 p.m. | Last Modified: 11 Dec 2025, 5:32 p.m.

Panel Version: 1.8

Green List (high evidence)

Comment on publications: https://doi.org/10.1182/blood-2024-210339 does not have a PMID number yet

Created: 12 May 2025, 4:56 p.m. | Last Modified: 12 May 2025, 4:56 p.m.

Panel Version: 1.6

Numerous SH2B3 variants are associated with myeloproliferative neoplasms (PMID: 28484264; 27237057). In the myeloproliferative neoplasms, the SH2B3 variants can be germline or somatic within the neoplasm. Germline homozygous SH2B3 variants are also associated with acute lymphoblastic leukemia (PMID: 23908464).

Created: 12 May 2025, 4:53 p.m. | Last Modified: 12 May 2025, 4:53 p.m.

Panel Version: 1.5

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Publications

• 28484264
• 27237057
• 23908464

Green List (high evidence)

Discussed at UKCGG/CanGene-CanVar national consensus meeting on somatic>germline testing pathways in haematological malignancies - consensus from stakeholders that germline SH2B3 testing should be available in patient with relevant clinical phenotypes to inform clinical entity, disease course and onward management.

Created: 30 Apr 2025, 10:20 a.m. | Last Modified: 30 Apr 2025, 10:20 a.m.

Panel Version: 1.5

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
thrombocytosis; myeloproliferative disease; ALL

Publications

• https://doi.org/10.1182/blood-2024-210339

Red List (low evidence)

Limited evidence of SH2B3 (alson known as LNK) variants associated with Thrombocythaemia. Most reporting on Thrombocythaemia are in adjacent to work on Myeloproliferative neoplasms (MPNs) - these are a heterogenous group of malignant haematological disorder, of which one of the seven diagnostic entities is Essential Thrombocythaemia.
• PMID 20404132 identifies a patient with thrombocythaemia with a somatic variant (E208Q) in SH2B3 when investigating patients with myeloproliferative neoplasms the patient did not have the known JAK2 (V617F) somatic variant. The role of CALR had not been discovered at this time
• PMID: 27237057 Aimed to discover new variants associated with familial forms of MPN's, 26 members from five families sequenced with at least two members affected by MPN. A proband who had primary myelofibrosis phenotype had the E208Q SH2B3 variant and a CALR variant (p.L367fs*46) were identified. The probands daughter had a thrombocythaemia phenotype with the same SH2B3 variant and the JAK2 (V617F) variant. Three additional family members had the SH2B3 variant but no reported associated phenotypes. Although the E208Q SH2B3 variant is germline there is not sufficient evidence that this variant causes a thrombocythaemia phenotype.
• PMID 27716218 also identified variant E208Q in SH2B3 and concluded it as a germline variant. Two unrelated families each had two family members with MPNs and the E208Q in SH2B3 variant. Only 2/4 with MPNs had thrombocythaemia all had the JAK2 (V617F) variant, the authors concluded that it appears unlikely that SH2B3 alterations may act as driver mutations in MPNs.
Therefore rating SH2B3 as Amber as although germline variants have been discovered the Thromobcythaemia phenotype has only been observed when accompanied with additional known somatic variants in JAK2/CALR

Created: 28 Sep 2020, 3:43 p.m. | Last Modified: 28 Sep 2020, 4:24 p.m.

Panel Version: 0.8

Mode of inheritance
Other

Publications

• 20404132
• 27716218
• 27237057

Tagging for GMS expert review to determine whether this gene should be included and the MOI that should be set on this panel. Both germline and somatic variants have been reported - MOI currently set to Other to capture somatic origin.

Terri McVeigh states that this gene should be included on the panel, although thrombocythaemia typically presents alongside myeloproliferative neoplasm. Testing criteria for this panel states that secondary causes such as myeloproliferative neoplasm should be excluded.

Created: 2 Jul 2025, 10:52 a.m. | Last Modified: 2 Jul 2025, 10:52 a.m.

Panel Version: 1.6

This gene has been added to the panel on the recommendation of GMS specialist disease group experts. Rating Amber as only somatic variants are reported in this gene.

Created: 20 Aug 2020, 2:55 p.m. | Last Modified: 20 Aug 2020, 2:55 p.m.

Panel Version: 0.1

Mode of inheritance
Unknown