Hereditary Erythrocytosis

Gene: SH2B3

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: 4 Apr 2025, 12:25 p.m. | Last Modified: 4 Apr 2025, 12:25 p.m.

Panel Version: 2.11

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
thrombocytosis; myeloproliferative disease; ALL

Publications

• https://doi.org/10.1182/blood-2024-210339
• 10.1016/j.ejcped.2023.100042
• PMID: 38024597
• PMID: 37981895
• https://doi.org/10.1182/blood-2013-08-519843
• https://doi.org/10.1016/j.leukres.2024.107566https://doi.org/10.1182/blood-2013-05-500850

After NHS Genomic Medicine Service consideration, the rating of this gene has not been changed and remains amber. The GMS reviewers commented as follows: All GLH providers for this specialty agree that this should not be promoted to green rating - no definitive evidence for germline association with erythrocytosis

Created: 10 Dec 2025, 2:38 p.m. | Last Modified: 10 Dec 2025, 2:38 p.m.

Panel Version: 2.15

Tagging for GMS expert review to determine whether this gene should be included and the MOI that should be set on this panel. Erythrocytosis is thought to be caused by somatic variants (for somatic variants MOI is set to Other) and testing criteria for this panel states that secondary causes such as myeloproliferative neoplasm should be excluded. However, Terri McVeigh states that germline variants should be included, although these are typically linked to myeloproliferative neoplasms.

Cases of erythrocytosis due to germline variants are rare, and most studies reporting SH2B3 variants have not determined germline or somatic status (PMID: 20843259; 23812944; 27651169; 34349782). In the literature, there is only one report of idiopathic erythrocytosis, without signs of myeloproliferative neoplasms, associated with a confirmed germline heterozygous SH2B3 variant. The mother was also a carrier but had no signs of erythrocytosis (PMID: 38024597).

Created: 2 Jul 2025, 10:40 a.m. | Last Modified: 2 Jul 2025, 10:40 a.m.

Panel Version: 2.13

Eligibility criteria for this panel (R405) states that secondary causes of erythrocytosis such as myeloproliferative neoplasm must be excluded prior to testing.

Created: 10 Dec 2021, 2:40 p.m. | Last Modified: 10 Dec 2021, 2:41 p.m.

Panel Version: 1.42

Publications

• 20843259
• 23812944
• 27651169
• 34349782
• 38024597

I don't know

Germline variants in this gene are well-known cause of familial myeloproliferative neoplasm, which usually presents with erythrocytosis. Both expert reviews suggests SH2B3 variant testing for JAK2-negative erythrocytosis.

Created: 30 Nov 2021, 9:42 p.m. | Last Modified: 30 Nov 2021, 9:42 p.m.

Panel Version: 1.35

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Myeloproliferative neoplasm

Publications

• PMID: 34440325
• 34021251

Red List (low evidence)

SH2B3 also known as LNK in literature. SH2B3 variants identified in JAK2 negative erythrocytosis
PMID 20843259 identified two patients with variants in the PH domain. A missense variant (644C→T, [A215V]) and a nonsense variant (622G→T, [E208X]). The E208X variant has also been identified previously and reported with an association with Thrombocythemia. Limited patient details reported.
PMID: 23812944 Identified six patients with idiopathic erythrocytosis although due to lack of parental samples unable to determine inheritance.
In both papers variants were for the idiopathic form of erythrocytosis, no details were given about familial erythrocytosis. Therefore rating as Red as not enough evidence for a gene disease relationship between SH2B3 and Hereditary Erythrocytosis.

Created: 28 Sep 2020, 10:04 a.m. | Last Modified: 28 Sep 2020, 10:04 a.m.

Panel Version: 1.16

Mode of inheritance
Other

Phenotypes
Hereditary Erythrocytosis

Publications

• 23812944
• 20843259

Green List (high evidence)

Based on the review by Terri McVeigh (Royal Marsden NHS Foundation Trust), this gene is recommended to be made green.

Created: 8 Apr 2025, 11:10 a.m. | Last Modified: 8 Apr 2025, 11:10 a.m.

Panel Version: 2.13

Comment on list classification: An amber rating has been given to SH2B3, as only somatic variants in this gene have been reported to be associated with Erythrocytosis, somatic 133100.

Created: 22 Sep 2020, 3:16 p.m. | Last Modified: 22 Sep 2020, 3:16 p.m.

Panel Version: 1.13

GMS Expert review Green
Sources: NHS GMS, Expert review

Created: 18 Aug 2020, 4:28 p.m. | Last Modified: 18 Aug 2020, 4:33 p.m.

Panel Version: 1.8

Mode of inheritance
Unknown

Phenotypes
Erythrocytosis, somatic 133100