Haematological malignancies cancer susceptibility

Gene: HAVCR2

Green List (high evidence)

Comment on list classification: There are three different variants reported in patients from multiple descents - the p.Tyr82Cys variant occurs on a potential founder chromosome in patients with East Asian and Polynesian descent, while p.Ile97Met occurs in patients with European ancestry.

Expert opinion is sought from the Genomic Medicine Service on whether this gene can be promoted to green rating in the next GMS update.

Created: 27 Oct 2025, 11:17 a.m. | Last Modified: 27 Oct 2025, 5:03 p.m.

Panel Version: 4.33

Comment on phenotypes: This gene is associated with relevant phenotypes in OMIM (MIM #618398, OMIM accessed on 27 October 2025) and in Gene2Phenotype ('definitive' rating on Skin Panel).

Biallelic variants in this gene are also associated with HAVCR2-related cancer predisposition (MONDO:1060169) with 'moderate' rating by Childhood, Adolescent and Young Adult Cancer Predisposition expert panel in ClinGen.

Created: 27 Oct 2025, 11:14 a.m. | Last Modified: 27 Oct 2025, 11:14 a.m.

Panel Version: 4.27

PMID:30374066 (2018) reported the identification of germline homozygous missense variant (p.Tyr82Cys) in nine patients from seven unrelated families of East Asian or Polynesian descent with subcutaneous panniculitis-like T cell lymphoma (SPTCL). In addition, there were two unrelated patients of European descent with SPTCL were identified with homozygous missense variant, p.Ile97Met, of which germline status was confirmed in one patient. The same p.Ile97Met was identified in heterozygous state in one additional patient with SPTCL. An SPTCL patient of North African descent was identified with both variants (p.Tyr82Cys & p.Ile97Met) at compound heterozygous state from tumour tissue, where no germline DNA was available for testing.

PMID:30792187 (2019) reported patients of Asian descent with SPTCL, of which 10 patients were identified with the same p.Tyr82Cys variant in homozygous state and one patient was identified with p.Tyr82Cys/ p.Thr101Ile variants in compound heterozygous state.

PMID:32005988 (2020) reported a retrospective study of 70 SPTCL cases, of which 13 patients had HAVCR2 variants - six with p.Ile97Met.

PMID:32285995 (2020) reported a patient with SPTCL identified with compound heterozygous variants - p.Ile97Met & p.Thr101Ile.

Created: 27 Oct 2025, 11:09 a.m. | Last Modified: 27 Oct 2025, 11:09 a.m.

Panel Version: 4.25

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
T-cell lymphoma, subcutaneous panniculitis-like, OMIM:618398; subcutaneous panniculitis-like T-cell lymphoma, MONDO:0019475

Publications

• 30374066
• 30792187
• 32005988
• 32285995

Green List (high evidence)

PMID: 30374066
"The variant encoding p.Tyr82Cys TIM-3 occurs on a potential founder chromosome in patients with East Asian and Polynesian ancestry, while p.Ile97Met TIM-3 occurs in patients with European ancestry. Both variants induce protein misfolding and abrogate TIM-3’s plasma membrane expression, leading to persistent immune activation and increased production of inflammatory cytokines, including tumor necrosis factor-α and interleukin-1β, promoting HLH and SPTCL."

Created: 9 Aug 2024, 8:36 a.m. | Last Modified: 9 Aug 2024, 8:36 a.m.

Panel Version: 4.5

From PMID: 32005988:
Homozygous p.Ile97Met variant was found in subcutaneous panniculitis-like T-cell lymphoma (SPTCL) patients with European ancestry, 1 patient from North Africa, and patient from Reunion Island.
Sources: Expert list, Expert Review, Literature

Created: 9 Aug 2024, 8:23 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
T-cell lymphoma, subcutaneous panniculitis-like (OMIM: 618398)

Publications

• PMID: 32005988
• 30374066

Mode of pathogenicity
Other

Variants in this GENE are reported as part of current diagnostic practice