Haematological malignancies cancer susceptibility

Gene: ERCC6L2

Green List (high evidence)

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

Created: 30 Jan 2023, 11:21 a.m. | Last Modified: 30 Jan 2023, 11:21 a.m.

Panel Version: 3.3

Changed the tags from Q3_22 to Q2_22 as this review is in the batch with the other Q2_22 tagged genes.

Created: 8 Jun 2022, 11:25 p.m. | Last Modified: 8 Jun 2022, 11:25 p.m.

Panel Version: 2.33

Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.

Created: 7 Jun 2022, 2:45 p.m. | Last Modified: 7 Jun 2022, 2:45 p.m.

Panel Version: 2.31

Green List (high evidence)

ERCC6L2 is a relatively recently discovered gene in which biallelic germline LOF variants are associated with bone marrow failure syndrome and this gene already has green status is cytopenia panels on PanelApp.

Over the last 3 years, with more widespread testing, it has become apparent that in addition to being associated with bone marrow failure it is also associated with the development of MDS / AML with the acquisition of pathogenic variants in the TP53 gene (lack of ERCC6L2 results in defects in the transcription-coupled nucleotide excision repair pathway, leading to genome instability).

Initially described in Finland, a presentation at the American Society of Haematology 2021 https://doi.org/10.1182/blood-2021-145039 illustrated that there are a number of cases in other European countries now reported. I am aware that cases have also been detected within the GMS; the cytopenia panel has demonstrated the germline mutations, whereas these were not highlighted on the WGS performed for the subsequent AML owing to the fact the gene is not currently included on the applied germline panel.

Detection of this germline variant is critical to management of these patients as currently it would mean an allogeneic HSCT is required (and as with any germline variant there would be implications for related donor choice).
Sources: Literature

Created: 6 Jun 2022, 8:34 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Bone marrow failure syndrome 2, 615715; MDS; AML

Publications

• PMID: 30936069
• PMID: 31221794

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