| Date | Panel | Item | Activity | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Inherited predisposition to acute myeloid leukaemia (AML) v2.3 | MBD4 |
Achchuthan Shanmugasundram changed review comment from: 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.; to: 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. Notes from GMS reviewers: MBD4 is associated with a rare cancer predisposition syndrome with high penetrance for AML. Loss of function of the gene results in defective base excision repair and a mutator phenotype. It is appropriate to include this gene in the panel. Agree with the evidence cited, would seek consensus approval with CGG. As the reports for variants in this gene are limited, it may be prundent to restrict analysis to clearly LOF truncating variants in the first instance. Reagents would require redesign for this gene to be included. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Inherited predisposition to acute myeloid leukaemia (AML) v2.3 | MBD4 |
Achchuthan Shanmugasundram Tag Q3_22_rating was removed from gene: MBD4. Tag Q3_22_NHS_review was removed from gene: MBD4. Tag Q3_22_expert_review was removed from gene: MBD4. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Inherited predisposition to acute myeloid leukaemia (AML) v2.3 | MBD4 | Achchuthan Shanmugasundram reviewed gene: MBD4: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Inherited predisposition to acute myeloid leukaemia (AML) v2.2 | MBD4 |
Achchuthan Shanmugasundram Source Expert Review Green was added to MBD4. Source NHS GMS was added to MBD4. Rating Changed from Amber List (moderate evidence) to Green List (high evidence) |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Inherited predisposition to acute myeloid leukaemia (AML) v1.24 | MBD4 |
Arina Puzriakova changed review comment from: Comment on list classification: This gene will be flagged for GMS expert review to determine the suitability of MBD4 for malignancy predisposition testing. MBD4 was first added by an external reviewer to the 'Haematological malignancies cancer susceptibility' panel (https://panelapp.genomicsengland.co.uk/panels/59/gene/MBD4/), however after GMS consideration it was decided that it should remain amber (v2.23). Loss of MBD4 leads to an accumulation of somatic CpG>TpG transitions, consistent with MBD4 function which involves repair of G:T mismatches resulting from deamination of 5'-methylcytosine. Germline MBD4 inactivation can therefore lead to somatic variation (i.e. CpG>TpG) in well-down cancer driver genes, in turn conferring cancer susceptibility. Although MBD4 itself does not directly drive oncogenesis, evidence suggests it may modify disease risk as shown by multiple cases reported in literature with this distinctive mutational signature. Given that there are now two separate Green clinical reviews suggesting this gene, it will again be flagged for further GMS review.; to: Comment on list classification: This gene will be flagged for GMS expert review to determine the suitability of MBD4 for malignancy predisposition testing. MBD4 was first added by an external reviewer to the 'Haematological malignancies cancer susceptibility' panel (https://panelapp.genomicsengland.co.uk/panels/59/gene/MBD4/), however after GMS consideration it was decided that it should remain amber (v2.23). Loss of MBD4 leads to an accumulation of somatic CpG>TpG transitions, consistent with MBD4 function which involves repair of G:T mismatches resulting from deamination of 5'-methylcytosine. Germline MBD4 inactivation can therefore lead to somatic variation (i.e. CpG>TpG) in well-known cancer driver genes, in turn conferring cancer susceptibility. Although MBD4 itself does not directly drive oncogenesis, evidence suggests it may modify disease risk as shown by multiple cases reported in literature with this distinctive mutational signature. Given that there are now two separate Green clinical reviews suggesting this gene, it will again be flagged for further GMS review. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Inherited predisposition to acute myeloid leukaemia (AML) v1.24 | MBD4 | Arina Puzriakova Classified gene: MBD4 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Inherited predisposition to acute myeloid leukaemia (AML) v1.24 | MBD4 |
Arina Puzriakova Added comment: Comment on list classification: This gene will be flagged for GMS expert review to determine the suitability of MBD4 for malignancy predisposition testing. MBD4 was first added by an external reviewer to the 'Haematological malignancies cancer susceptibility' panel (https://panelapp.genomicsengland.co.uk/panels/59/gene/MBD4/), however after GMS consideration it was decided that it should remain amber (v2.23). Loss of MBD4 leads to an accumulation of somatic CpG>TpG transitions, consistent with MBD4 function which involves repair of G:T mismatches resulting from deamination of 5'-methylcytosine. Germline MBD4 inactivation can therefore lead to somatic variation (i.e. CpG>TpG) in well-down cancer driver genes, in turn conferring cancer susceptibility. Although MBD4 itself does not directly drive oncogenesis, evidence suggests it may modify disease risk as shown by multiple cases reported in literature with this distinctive mutational signature. Given that there are now two separate Green clinical reviews suggesting this gene, it will again be flagged for further GMS review. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Inherited predisposition to acute myeloid leukaemia (AML) v1.24 | MBD4 | Arina Puzriakova Gene: mbd4 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Inherited predisposition to acute myeloid leukaemia (AML) v1.23 | MBD4 |
Arina Puzriakova Tag Q3_22_rating tag was added to gene: MBD4. Tag Q3_22_NHS_review tag was added to gene: MBD4. Tag Q3_22_expert_review tag was added to gene: MBD4. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Inherited predisposition to acute myeloid leukaemia (AML) v1.23 | MBD4 | Arina Puzriakova Phenotypes for gene: MBD4 were changed from polyposis; CRC; AML; MDS; UVM to Multi-organ tumour predisposition syndrome; Adenomatous colorectal polyposis; Colorectal cancer; Acute myeloid leukemia; Uveal melanoma | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Inherited predisposition to acute myeloid leukaemia (AML) v1.22 | MBD4 | Arina Puzriakova Publications for gene: MBD4 were set to 35460607 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Inherited predisposition to acute myeloid leukaemia (AML) v1.21 | MBD4 | Arina Puzriakova reviewed gene: MBD4: Rating: ; Mode of pathogenicity: None; Publications: 12417741, 30049810, 32239153, 35460607; Phenotypes: Multi-organ tumour predisposition syndrome, Adenomatous colorectal polyposis, Colorectal cancer, Acute myeloid leukemia, Uveal melanoma; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Inherited predisposition to acute myeloid leukaemia (AML) v1.21 | MBD4 |
Claire Palles gene: MBD4 was added gene: MBD4 was added to Inherited predisposition to acute myeloid leukaemia (AML). Sources: Literature Mode of inheritance for gene: MBD4 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MBD4 were set to 35460607 Phenotypes for gene: MBD4 were set to polyposis; CRC; AML; MDS; UVM Penetrance for gene: MBD4 were set to Complete Review for gene: MBD4 was set to GREEN Added comment: Bi-allelic carriers are at a high increased risk of colorectal polyposis, MDS/AML and uveal melanoma. Mono-allelic carriers are not at an increased risk of AML or polyposis in the data we have so far. Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||