Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

PMS2 : constitutional mismatch repair deficiency syndrome

HGNC:9122 | MONDO_0010159
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Expert Panel: Hereditary Cancer
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 6
13
12
De Rosa M et al. 2000 Mar 23 (PMID:10763829); De Vos M et al. 2004 May (PMID:15077197); Trimbath JD et al. 2001 (PMID:14574005); Auclair J et al. 2007 Nov (PMID:17557300); Etzler J et al. 2008 Feb (PMID:18030674);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5
Segregation Evidence   Summed LOD Family Count 1 1  
Candidate gene sequencing 3.83 1
De Vos M et al. 2004 May (PMID:15077197);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 3.83    
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); Wang Q et al. 1999 Jan 15 (PMID:9927034); Menko FH et al. 2004 (PMID:15340263);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 2 1
Auclair J et al. 2007 Nov (PMID:17557300); Etzler J et al. 2008 Feb (PMID:18030674);
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
Prolla TA et al. 1998 Mar (PMID:9500552); Chen PC et al. 2005 Oct 1 (PMID:16204034);
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 PMS2 gene with constitutional mismatch repair deficiency syndrome - a distinct disorder from Lynch syndrome - since the gene-disease relationship was first proposed by De Rosa et al., (2000). Multiple case level studies have been performed with cMMRD syndrome patients that have variants in the PMS2 gene. Other mismatch repair (MMR) genes MLH1, MSH2 and MSH6 also causes constitutional mismatch repair deficiency syndrome. IHC and western blot show absence of PMS2 protein in patient cells. Multiple PMS2 deficient mouse models have been established to show consistent phenotypes with cMMRD patients by developing lymphoma, leiomyosarcoma and myxoid liposarcoma. This evidence is consistent with a definitive relationship between the PMS2 gene and constitutional mismatch repair deficiency syndrome.