Inherited polyposis and early onset colorectal cancer - germline testing

Gene: GREM1

Green List (high evidence)

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

Created: 3 May 2024, 11:15 a.m. | Last Modified: 3 May 2024, 11:15 a.m.

Panel Version: 2.11

Green List (high evidence)

Comment on list classification: Following review by the specialist service group, it has been agreed that this gene should be rated as Green at the next GMS panel update.

Upregulation of GREM1 expression in colorectal mucosa has been linked to hereditary mixed polyposis syndrome.
Most described patients are carriers of the Ashkenazi founder variant, a 40-kb upstream duplication that spans the 3' end of the neighbouring SCG5 gene. However, there are other duplications of different sizes that have been associated with disease (and some don’t incorporate the 3’ end of SCG5).

There is currently no evidence of small variants or a whole gene duplication of GREM1 causing a similar phenotype.

There is sufficient evidence to support a definitive gene-disease relationship but the providing GLH need to account for the upstream sequence location and size of reported variants in their primer design (as R211 v2.10 is currently a purely wet-lab/non-WGS test).

Created: 11 Dec 2023, 12:14 p.m. | Last Modified: 13 Dec 2023, 11:06 a.m.

Panel Version: 2.10

Comment on phenotypes: Previous phenotypes:
Hereditary Mixed Polyposis Syndrome;Oligosyndactyly of the hands, Cenani-Linz-like (Dimitrov (2010) J Med Genet 47,569);Polyposis Syndrome, Hereditary Mixed, 1;Mixed polyposis syndrome (Jaeger (2012) Nat Genet 44,699);{Colorectal cancer, increased risk, association with}(Peters (2012) Hum Genet 131,217)

Created: 4 Jul 2023, 10 a.m. | Last Modified: 4 Jul 2023, 10 a.m.

Panel Version: 2.5

Publications

• 25992589
• 26947005
• 28242209
• 27984123
• 9024286
• 10092300
• 12696020
• 18084292
• 21128281
• 22561515
• 24586997
• 26493165
• 29804199
• 25419707

Green List (high evidence)

CNV calling for GREM1 is listed in the National Genomic test directory for R211.

Created: 25 May 2023, 2:36 p.m. | Last Modified: 25 May 2023, 2:36 p.m.

Panel Version: 2.4

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Mode of pathogenicity
Other

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

Comment on list classification: As discussed in the GMS Inherited Cancer Specialist Test Group webex call 31st Jan 2019: The Specialist Test Group agreed that this gene should be rated amber.

Created: 1 Feb 2019, 10:07 a.m.

Green List (high evidence)

Publications

• 29661970

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

Added 'duplication' and 'structural variant' tag.

Created: 11 May 2017, 10:26 a.m.

Comment on list classification: Only duplications, no evidence for SNVs having a role in disease. Keep under review as research evidence accumulates.

Created: 10 May 2016, 9:02 a.m.

Green List (high evidence)

Gain of function mutations, currently only large upstream duplications described

Created: 8 Dec 2015, 3:13 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Green List (high evidence)

Hereditary Mixed Polyposis Syndrome is caused by upregulation of GREM1 expression in colorectal mucosa, due to a 40-kb upstream duplication spanning the 3' end of the SCG5 gene.

Created: 8 Dec 2015, 2:36 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Hereditary Mixed Polyposis Syndrome

Publications

• Nat Genet. 2012 May 6
• 44(6):699-703. doi: 10.1038/ng.2263.

Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments