About PMS2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PMS2 c.736_741delinsTGTGTGTGAAG, p.(Pro246CysfsTer3)
Classification
Pathogenic
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is pathogenic. Select a step to read what it means.
Pathogenic.A pathogenic classification under the recorded framework.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is ClinGen PMS2 VCEP v2.0.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 3
Benign evidence criteria: 0
Pathogenic criteria applied · 3
PVS1Very strong
PVS1 · very strong
NM_000535.7:c.736_741delinsTGTGTGTGAAG is a frameshift indel in exon 7 introducing a premature termination codon at codon 248 (p.Pro246CysfsTer3). Under InSiGHT PMS2 VCEP v2.0.0, nonsense/frameshift variants introducing a PTC at codon ≤798 meet PVS1 at Very Strong strength. The PTC at codon 248 falls well within this boundary.
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0. Under InSiGHT PMS2 VCEP v2.0.0, PM2_Supporting is met when the allele frequency is <0.00002 (<1 in 50,000 alleles) in the gnomAD v4 dataset.
PP5Supporting
PP5 · supporting
Expert panel International Society for Gastrointestinal Hereditary Tumours (InSiGHT) classified as Pathogenic.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Pathogenic
ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PMS2 Version 2.0.0 v2.0.0 criteria-combination framework: matched Rule4 (1 Pathogenic.Very Strong + Pathogenic.Supporting >=2) with applied criteria: PVS1 very strong, PM2 supporting, PP5 supporting; maps to Pathogenic.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.050 maximum delta
Recorded SpliceAI maximum delta score: 0.050. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
24 reported laboratory submissions
24 Pathogenic. ClinVar API review status: reviewed by expert panel.
Functional evidence
Statement recorded
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under ClinGen PMS2 VCEP v2.0.0, with the data and sources behind each one.
28 criteria with recorded statuses: 3 met · 8 not met · 4 not assessed · 13 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_000535.7:c.736_741delinsTGTGTGTGAAG (p.Pro246CysfsTer3) is a frameshift indel in exon 7 of PMS2 that introduces a premature termination codon at amino acid position 248, meeting PVS1 at Very Strong strength under the InSiGHT PMS2 VCEP v2.0.0 (PTC ≤ codon 798).
The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0 population databases, meeting PM2_Supporting under InSiGHT PMS2 VCEP (allele frequency <0.00002).
This variant has been classified as Pathogenic by the InSiGHT expert panel (ClinVar variation ID 91366) and reported in 24 clinical laboratories as Pathogenic. It is a well-characterized founder mutation prevalent in Europe and North America, originally described by Clendenning et al. (2006) and extensively phenotyped by Senter et al. (2008) in 12 probands with Lynch syndrome-associated tumors showing isolated PMS2 loss by IHC.
No criteria match.
Met · 3
PVS1 Very strongNM_000535.7:c.736_741delinsTGTGTGTGAAG is a frameshift indel in exon 7 introducing a premature termination codon at codon 248 (p.Pro246CysfsTer3). Under InSiGHT PMS2 VCEP v2.0.0, nonsense/frameshift variants introducing a PTC at codon ≤798 meet PVS1 at Very Strong strength. The PTC at codon 248 falls well within this boundary. Details ▾Hide ▴
Evidence considered
- Frameshift indel introducing premature termination codon (PTC) at amino acid position 248
- PMS2 PTC threshold for PVS1_VeryStrong is ≤ codon 798 per InSiGHT VCEP v2.0.0
- PMS2 germline loss-of-function is an established disease mechanism for Lynch syndrome
Sources
PM2 SupportingThis variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0. Under InSiGHT PMS2 VCEP v2.0.0, PM2_Supporting is met when the allele frequency is <0.00002 (<1 in 50,000 alleles) in the gnomAD v4 dataset. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (exomes)
- Absent from gnomAD v4.1 (exomes)
- Absent from gnomAD-Canada v1.0 (genomes)
Sources
Not met · 8 · evaluated, threshold not reached
PS2 No de novo occurrence data were identified for this variant. PS2 under InSiGHT PMS2 VCEP v2.0.0 requires documented de novo points (0.5–≥4) in a proband with an MMR-deficient LS-spectrum tumor and confirmed maternity/paternity. Details ▾Hide ▴
Evidence considered
- No de novo observations found in review of full-text publications (16619239
- 18602922
- 20487569) or abstract-level sources
Still missing
- De novo status not assessed in available literature
PS3 No calibrated functional assay data with functional odds for pathogenicity are available for this specific variant. OncoKB classifies the variant as Likely Oncogenic based on curated literature, but the cited functional studies (PMID:10439048, PMID:10874005, PMID:12697830) are gene-level (PMS2 knockout mouse models, MutLα dimerization) and do not report variant-specific functional assays. Details ▾Hide ▴
Evidence considered
- OncoKB labels variant as Likely Oncogenic / Likely Loss-of-function but cites only gene-level functional evidence
- Variant-specific MMR functional assay data (e.g.
- in vitro MMR activity
- protein expression
- splicing assay) not available
Still missing
- No variant-specific calibrated functional assay data available
PP3 PP3 under InSiGHT PMS2 VCEP v2.0.0 applies to missense variants with MAPP/PP2 Prior P score >0.68 or non-canonical splice variants with SpliceAI delta ≥0.2. This variant is a frameshift indel, not a missense substitution. Additionally, SpliceAI predicts no splicing impact (max delta score = 0.05), and no HCI prior score is available for non-substitution variants. Details ▾Hide ▴
Evidence considered
- Variant is a frameshift indel
- not a missense substitution eligible for PP3
- SpliceAI max delta score = 0.05 (no splice impact)
- HCI prior not applicable for non-substitution variants
Sources
BA1 BA1 under InSiGHT PMS2 VCEP v2.0.0 requires gnomAD v4 Grpmax filtering allele frequency ≥0.0028 (0.28%). This variant is absent from all gnomAD population databases. BA1 is not met. Details ▾Hide ▴
Evidence considered
- Variant absent from gnomAD
- population frequency far below 0.28% threshold
Sources
BS1 BS1 under InSiGHT PMS2 VCEP v2.0.0 requires gnomAD v4 Grpmax filtering allele frequency ≥0.00028 (0.028%). This variant is absent from all gnomAD population databases. BS1 is not met. Details ▾Hide ▴
Evidence considered
- Variant absent from gnomAD
- population frequency far below 0.028% threshold
Sources
BS2 BS2 under InSiGHT PMS2 VCEP v2.0.0 requires documented co-occurrence in trans with a known pathogenic PMS2 variant in a colorectal cancer patient diagnosed after age 45 without clinical manifestations of CMMRD. No such evidence was identified. Details ▾Hide ▴
Evidence considered
- No co-occurrence data meeting BS2 criteria available
Still missing
- Trans co-occurrence data with pathogenic PMS2 variant would be needed to apply BS2
BS3 No calibrated functional assay data demonstrating functional odds for pathogenicity ≤0.48 or variant-specific proficient function are available. OncoKB labels the variant as Likely Oncogenic/Likely Loss-of-function, inconsistent with a benign functional readout. Details ▾Hide ▴
Evidence considered
- OncoKB classifies variant as Likely Loss-of-function
- contrary to BS3
- No variant-specific functional data demonstrating benign effect
Still missing
- No variant-specific functional benign evidence available
BS4 No lack-of-segregation data available. BS4 requires combined Bayes Likelihood Ratio <0.48 from co-segregation analysis. No segregation evidence was provided in the case materials. Details ▾Hide ▴
Evidence considered
- No segregation data available
Still missing
- Segregation analysis required for BS4 evaluation
Not assessed · 4 · no assessment recorded
PP1 No co-segregation data (pedigrees with Bayes Likelihood Ratio) were available in the case materials to evaluate PP1. Details ▾Hide ▴
Evidence considered
- No segregation analysis data provided in case packet
Still missing
- Co-segregation analysis requires pedigree data with genotype-phenotype information
PP4 No patient-specific tumor MSI or IHC data were available in the case materials to evaluate PP4. Published literature (PMID:18602922) reports that this variant was identified in probands selected by isolated PMS2 loss on IHC, with tumors showing MSI-H, satisfying at least PP4_Supporting in those individuals. However, without patient-specific data for the case under adjudication, PP4 cannot be formally applied. Details ▾Hide ▴
Evidence considered
- Published literature confirms variant was identified in 12 probands with isolated PMS2 loss on IHC (PMID:18602922)
- No patient-specific tumor phenotype data in case packet
Still missing
- Patient-specific tumor MSI/IHC results needed to apply PP4
BP5 No patient-specific tumor data (MSS status, IHC results, BRAF V600E, or MLH1 methylation testing) were available in the case materials. Published data (PMID:18602922) notes BRAF V600E was identified in 2 of 47 tested probands with the c.736_741del6ins11 variant, but tumor context details (MSI-H status, MLH1 methylation) are not fully specified, precluding definitive BP5 application. Details ▾Hide ▴
Evidence considered
- PMID:18602922 reports BRAF V600E in 2 of 47 tumors from probands with this variant
- but tumor phenotype context insufficient for BP5
Still missing
- Patient-specific tumor MSI/IHC/BRAF/methylation data needed to evaluate BP5
PS5 No evidence available to evaluate PS5 (variant found by an established reputable source but with no independent evidence available in this case packet). Details ▾Hide ▴
Still missing
- No PS5-specific evidence in case materials
Not applicable · 13· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 under InSiGHT PMS2 VCEP v2.0.0 applies to predicted missense substitutions sharing the same amino acid change as a known pathogenic variant, or non-canonical splice site variants with comparable splicing prediction. This variant is a frameshift indel, not a missense substitution or splice variant. Details ▾Hide ▴
No further detail was recorded.
PS4 VCEPPS4 is listed as Not Applicable under InSiGHT PMS2 VCEP v2.0.0. Details ▾Hide ▴
Sources
PM1 VCEPPM1 is listed as Not Applicable under InSiGHT PMS2 VCEP v2.0.0. Details ▾Hide ▴
Sources
PM4 VCEPPM4 is listed as Not Applicable under InSiGHT PMS2 VCEP v2.0.0. Details ▾Hide ▴
Sources
PM5 N/APM5 under InSiGHT PMS2 VCEP v2.0.0 applies only to missense changes at an amino acid residue where a different missense change has been classified as Pathogenic or Likely Pathogenic. This variant is a frameshift indel, not a missense change. Details ▾Hide ▴
No further detail was recorded.
PM6 VCEPPM6 is listed as Not Applicable under InSiGHT PMS2 VCEP v2.0.0. Details ▾Hide ▴
Sources
PP2 VCEPPP2 is listed as Not Applicable under InSiGHT PMS2 VCEP v2.0.0. Details ▾Hide ▴
Sources
BP1 VCEPBP1 is listed as Not Applicable under InSiGHT PMS2 VCEP v2.0.0. Details ▾Hide ▴
Sources
BP2 VCEPBP2 is listed as Not Applicable under InSiGHT PMS2 VCEP v2.0.0. Details ▾Hide ▴
Sources
BP3 VCEPBP3 is listed as Not Applicable under InSiGHT PMS2 VCEP v2.0.0. Details ▾Hide ▴
Sources
BP4 N/ABP4 under InSiGHT PMS2 VCEP v2.0.0 applies to (a) missense variants with MAPP/PP2 Prior P score <0.11, or (b) intronic and synonymous variants with SpliceAI delta ≤0.1. This variant is a frameshift coding indel and does not fall within either category. BP4 is not applicable. Details ▾Hide ▴
No further detail was recorded.
BP6 VCEPBP6 is listed as Not Applicable under InSiGHT PMS2 VCEP v2.0.0. Details ▾Hide ▴
Sources
BP7 N/ABP7 under InSiGHT PMS2 VCEP v2.0.0 applies to synonymous (silent) or intronic variants at or beyond -21/+7. This variant is a frameshift coding indel in exon 7 and does not fall within the scope of BP7. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- PMS2
- Transcript
- NM_000535.7
- Coding (HGVS c.)
- NM_000535.7:c.736_741delinsTGTGTGTGAAG
- Protein (HGVS p.)
- NP_000526.2:p.(Pro246CysfsTer3)
- GRCh38
- chr7:5997388 AGGGGG>CTTCACACACA
- GRCh37
- chr7:6037019 AGGGGG>CTTCACACACA
- ClinVar
- 91366, 9234
Gene diagram
Every interpreted variant in PMS2, mapped onto the exon structure of NM_000535.7. Select a row to find it on the plot.
PMS2NM_000535.7
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in PMS2
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 PP3 under InSiGHT PMS2 VCEP v2.0.0 applies to missense variants with MAPP/PP2 Prior P score >0.68 or non-canonical splice variants with SpliceAI delta ≥0.2. This variant is a frameshift indel, not a missense substitution. Additionally, SpliceAI predicts no splicing impact (max delta score = 0.05), and no HCI prior score is available for non-substitution variants. Details ▾Hide ▴
Evidence considered
- Variant is a frameshift indel
- not a missense substitution eligible for PP3
- SpliceAI max delta score = 0.05 (no splice impact)
- HCI prior not applicable for non-substitution variants
Sources
BP4 N/ABP4 under InSiGHT PMS2 VCEP v2.0.0 applies to (a) missense variants with MAPP/PP2 Prior P score <0.11, or (b) intronic and synonymous variants with SpliceAI delta ≤0.1. This variant is a frameshift coding indel and does not fall within either category. BP4 is not applicable. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ABP7 under InSiGHT PMS2 VCEP v2.0.0 applies to synonymous (silent) or intronic variants at or beyond -21/+7. This variant is a frameshift coding indel in exon 7 and does not fall within the scope of BP7. Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.05).
8 paper records listed. 4 cited in the classification.
Cited in the classification
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PMID 16619239 ↗Long-range PCR facilitates the identification of PMS2-specific mutations.Clendenning M et al. · 2006 MayFirst reported identification of c.736_741del6ins11 (p.P246FfsX7) as a novel deleterious PMS2 mutation. Detected in a colorectal cancer cohort screened by long-range PCR; described as one of four strong candidate deleterious mutations among five novel mutations identified.→ PVS1 Names this variant
Source detail
Of these changes, four (c.705+1G>T, c.862_863del, c.736_741del6ins11, and c.2007-1G>A) are strong candidates for being deleterious.
Location Abstract; Results paragraph 3; Figure 1c; Table 2
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PMID 18178629 ↗A frame-shift mutation of PMS2 is a widespread cause of Lynch syndrome.Clendenning M et al. · 2008 JunCharacterizes the c.736_741del6ins11 PMS2 frameshift mutation as a widespread founder cause of Lynch syndrome. The paper describes its prevalence and likely origin.→ PVS1 Names this variant
Source detail
A frame-shift mutation of PMS2 is a widespread cause of Lynch syndrome.
Location Title and abstract
-
PMID 18602922 ↗The clinical phenotype of Lynch syndrome due to germ-line PMS2 mutations.Senter L et al. · 2008 AugComprehensive clinical characterization of PMS2 mutation carriers. The c.736_741del6ins11 (P246CfsX3) frameshift mutation was the most frequently observed PMS2 mutation, found in 12 ostensibly unrelated probands with Lynch syndrome-associated tumors showing isolated PMS2 loss on IHC. Founder haplotype analysis traced the mutation to the first millennium, likely originating in Sweden or England. Among 47 probands tested for BRAF, two c.736_741del6ins11 carriers harbored the BRAF V600E mutation.→ PVS1 Names this variant
Source detail
The most notable of the 5 exceptions was an insertion/deletion frameshift mutation in exon 7, which was seen in 12 ostensibly unrelated probands.
Location Results (Figure 1; Table 1); BRAF Results paragraph
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PMID 20487569 ↗MSH6 and PMS2 mutation positive Australian Lynch syndrome families: novel mutations, cancer risk and age of diagnosis of colorectal cancer.Austrian Lynch syndrome study reporting PMS2 mutations. The c.736_741del6ins11 mutation was identified in three PMS2 families: CRC diagnosed at ages 41 and 47 years, and one cancer-free carrier at age 67. Described as a truncating mutation previously reported.→ PVS1 Names this variant
Source detail
Family PMS2_1, PMS2_2, PMS2_5: c.736_741del6ins11, Truncating
Location Table 4: PMS2 probands mutation list
Other recorded publications
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PMID 10439048 ↗Mice defective in the DNA mismatch gene PMS2 are hypersensitive to MNU induced thymic lymphoma and are partially protected by transgenic expression of human MGMT.Mouse PMS2 knockout study examining sensitivity to MNU-induced thymic lymphoma and protection by transgenic MGMT expression. No human PMS2 variants mentioned.Does not name this variant
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PMID 10874005 ↗Mutagenesis in PMS2- and MSH2-deficient mice indicates differential protection from transversions and frameshifts.Mutagenesis comparison in PMS2- and MSH2-deficient mice examining mutation frequency and spectra. Gene-level study; no human PMS2 variants mentioned.Does not name this variant
-
PMID 12697830 ↗Dimerization of MLH1 and PMS2 limits nuclear localization of MutLalpha.Study of MLH1-PMS2 dimerization and its role in nuclear localization of MutLα. No human PMS2 variants mentioned.Does not name this variant
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PMID 16144131 ↗Two PMS2 mutations in a Turcot syndrome family with small bowel cancers.Turcot syndrome family reported with two different PMS2 mutations: Q643X (nonsense in exon 11) and S46I (missense in exon 2). The c.736_741delinsTGTGTGTGAAG variant is not described in this paper.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.050
Open source ↗
ClinVar
24 Pathogenic
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
ClinGen CSpec
Captured ClinGen CSpec source record
Open source ↗
All source links
- ClinGen CSpec ↗cspec.genome.network/cspec/ui/svi/doc/1578297058
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/91366/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/7-6037019-AGGGGG-CTTCACACACA?…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr7-5997388-AGGGGG-CTTCACACA…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/7-5997388-AGGGGG-CTTCACACACA
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000535.7%3Ac.736_…
- OncoKB ↗www.oncokb.org/gene/PMS2/P246Cfs*3
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=PMS2+c.736_741delinsTGTGTGTGAAG
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Pathogenic (24 clinical laboratories) and as Pathogenic by International Society for Gastrointestinal Hereditary Tumours (InSiGHT) (expert panel). (ClinVarID = 91366)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.05).
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.