Gene Validity Classification Summary

Gene/Disease Pair:

PTPRJ : hereditary nonpolyposis colon cancer

HGNC:9673 | MONDO_0018630
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
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
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5
Segregation Evidence   Summed LOD Family Count  
Candidate gene sequencing
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score    
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) 0
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2 1
Zhang XF et al. 2017 Oct (PMID:28316102);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4
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) 1.5



Assertion criteria Genetic Evidence (0-12 points) Experimental Evidence
(0-6 points)
Total Points
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
> 2 pubs w/ convincing evidence over time (>3 yrs)
Assigned Points 0 1.5 1.5 NO
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
In addition to experimental evidence, there has been 1 report in the literature with an individual harboring a PTPRJ variant (Venkatachalam, 2010; PMID: 21036128). This individual has a 5' duplication of exons 1-11 of PTPRJ, located directly upstream of the wild-type gene. This was assigned 0.5 points for genetic evidence, bringing the total points to 2.0 with a classification of "Limited." The relationship between PTPRJ and Hereditary Nonpolyposis Colon Cancer (autosomal dominant) was evaluated using the ClinGen Clinical Validity Framework as of 10-9-2018 (SOP Version 6.0). Variants in PTPRJ were first reported in humans with this disease as early as 2010 (Venkatachalam et al). At least 1 variant (multi exon duplication) has been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Summary of Case Level Data: 0.5 Points. A multi-exon duplication in this gene has been reported in at least 1 proband. Experimental Evidence: 1.5 Points. This gene-disease association is supported by biochemical function. In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship.