Gene Validity Classification Summary

Gene/Disease Pair:

MLH1 : constitutional mismatch repair deficiency syndrome

HGNC:7127 | MONDO_0010159
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Expert Panel: Hereditary Cancer EP
SOP: Gene Clinical Validity Standard Operating Procedures (SOP), Version 6

Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Variant Evidence
Autosomal Dominant or X-linked Disorder Variant is de novo 2 0-3 12
Proband with predicted or proven null variant 1.5 0-2 10
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12 3
6.5
10.5
Ricciardone MD et al. 1999 Jan 15 (PMID:9927033); Vilkki S et al. 2001 Jun 1 (PMID:11389087); Poley JW et al. 2007 Jun 1 (PMID:17440981);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 4
4
Wang Q et al. 1999 Jan 15 (PMID:9927034); Baas AF et al. 2013 Jan (PMID:22692065); Raevaara TE et al. 2004 Jul (PMID:15139004); Gallinger S et al. 2004 Feb (PMID:14762794);
Segregation Evidence   Summed LOD Family Count 1.5 1.5  
Candidate gene sequencing 6.4 2
Ricciardone MD et al. 1999 Jan 15 (PMID:9927033); Gallinger S et al. 2004 Feb (PMID:14762794);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 6.4    
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Points PMIDs/Notes
Points/Study Max Count Points Counted
Single Variant Analysis 1. Variant Detection Methodology
2. Power
3. Bias and confounding
4. Statistical Significance
0-6 12
Aggregate Variant Analysis 0-6
Total Genetic Evidence Points (Maximum 12) 12
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2 3
1.5
2
Whiteside D et al. 2002 Jan 15 (PMID:11809679); De Rosa M et al. 2000 Mar 23 (PMID:10763829); Menko FH et al. 2004 (PMID:15340263);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 1 0.5
Poley JW et al. 2007 Jun 1 (PMID:17440981);
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 2 4 4
Feitsma H et al. 2008 Jul 1 (PMID:18593904); Prolla TA et al. 1998 Mar (PMID:9500552);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4
Rescue in cell culture model 1 0 - 2
Rescue in patient cells 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 6

 


 

Assertion criteria Genetic Evidence (0-12 points) Experimental Evidence
(0-6 points)
Total Points
(0-18)
Replication Over Time (Y/N)
Description Case-level, family segregation, or case-control data that support the gene-disease association Gene-level experimental evidence that support the gene-disease association Sum of Genetic & Experimental
Evidence
> 2 pubs w/ convincing evidence over time (>3 yrs)
Assigned Points 12 6 18 YES
CALCULATED CLASSIFICATION LIMITED 1-6
MODERATE 7-11
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
NO
CALCULATED CLASSIFICATION (DATE)
Definitive
10/09/2018
EXPERT CURATION (DATE)
Definitive
10/09/2018
EVIDENCE SUMMARY
There is sufficient evidence published associating the MLH1 gene with constitutional mismatch repair deficiency syndrome - a distinct disorder from Lynch syndrome - since the gene-disease relationship was first proposed by Wang et al., (1999). Multiple case level studies have been performed with cMMRD patients that have variants in the MLH1 gene. Other mismatch repair (MMR) genes MSH2, MSH6 and PMS2 also causes constitutional mismatch repair deficiency syndrome. Patients' tumors and normal tissue were both negative for MLH1 protein. Multiple MLH1 deficient mouse and zebrafish models have been established to show consistent phenotypes with cMMRD patients by developing neurofibromas, lymphoma, gastrointestinal carcinoma and skin tumors. This evidence is consistent with a definitive relationship between the MLH1 gene and constitutional mismatch repair deficiency syndrome.