About PMS2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PMS2 c.1321G>T, p.(Glu441Ter)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
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. 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: 2
Benign evidence criteria: 0
Pathogenic criteria applied · 2
PVS1Very strong
PVS1 · very strong
Nonsense variant NM_000535.6:c.1321G>T introduces a premature termination codon at position 441 (p.Glu441Ter), which is ≤ codon 798. Per InSiGHT PMS2 VCEP v2.0, nonsense/frameshift variants introducing a PTC ≤ codon 798 meet PVS1 at Very Strong strength.
PM2Supporting
PM2 · supporting
NM_000535.6:c.1321G>T is absent from gnomAD v2.1 and v4.1 (0 alleles). Per PMS2 VCEP v2.0, absence or extremely rare allele frequency (<0.00002, <1 in 50,000 alleles) in gnomAD v4 meets PM2 at Supporting strength.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PMS2 Version 2.0 v2.0 criteria-combination framework was evaluated deterministically with applied criteria: PVS1 very strong, PM2 supporting; no rule matched the adjudicated criteria.
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
0.030 maximum delta
Recorded SpliceAI maximum delta score: 0.030. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
1 reported laboratory submissions
1 Pathogenic. ClinVar API review status: criteria provided, single submitter.
Context only
ClinVar ↗
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, with the data and sources behind each one.
29 criteria with recorded statuses: 2 met · 10 not met · 0 not assessed · 17 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_000535.6:c.1321G>T (p.Glu441Ter) is a nonsense variant in PMS2 exon 11 introducing a premature termination codon at position 441, which is well before the VCEP-defined PVS1 boundary at codon 798.
This variant meets PVS1 at Very Strong strength under the InSiGHT PMS2 VCEP v2.0 criteria for nonsense variants introducing a PTC ≤ codon 798.
The variant is absent from gnomAD v2.1 and v4.1 population databases (0 alleles), meeting PM2 at Supporting strength under VCEP criteria (<0.00002 allele frequency threshold).
No variant-specific functional data, de novo observations, cosegregation data, or tumor phenotype data were identified in the case materials or reviewed literature.
SpliceAI predicts no significant splice impact (max delta 0.03), confirming that the primary molecular consequence is protein truncation rather than aberrant splicing.
Under the InSiGHT PMS2 VCEP v2.0 combination rules, 1 Very Strong criterion (PVS1) plus 1 Supporting criterion (PM2) is sufficient for a Pathogenic classification (Rule 1 or Rule 4).
No criteria match.
Met · 2
PVS1 Very strongNonsense variant NM_000535.6:c.1321G>T introduces a premature termination codon at position 441 (p.Glu441Ter), which is ≤ codon 798. Per InSiGHT PMS2 VCEP v2.0, nonsense/frameshift variants introducing a PTC ≤ codon 798 meet PVS1 at Very Strong strength. Details ▾Hide ▴
Evidence considered
- VCEP PVS1 rule: nonsense/frameshift PTC ≤ codon 798 in PMS2 → PVS1_VeryStrong
- Mutalyzer confirms c.1321G>T produces p.(Glu441Ter) with premature termination at codon 441 of 863
- SpliceAI max delta 0.03 — no cryptic splice rescue concern
Sources
PM2 SupportingNM_000535.6:c.1321G>T is absent from gnomAD v2.1 and v4.1 (0 alleles). Per PMS2 VCEP v2.0, absence or extremely rare allele frequency (<0.00002, <1 in 50,000 alleles) in gnomAD v4 meets PM2 at Supporting strength. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (0 alleles)
- Absent from gnomAD v4.1 (0 alleles)
- Absent from gnomAD-Canada v1.0 (0 alleles)
Sources
Not met · 10 · evaluated, threshold not reached
PS2 No de novo occurrence data for NM_000535.6:c.1321G>T is present in the case materials or literature reviewed. De novo points cannot be assigned without confirmed maternity and paternity in a proband with MMR-deficient LS-spectrum tumor. Details ▾Hide ▴
Evidence considered
- No de novo observations identified in ClinVar
- literature
- or case evidence
Still missing
- No de novo data available for this variant
PS3 No variant-specific functional data exists for NM_000535.6:c.1321G>T (p.Glu441Ter). The reviewed literature includes general PMS2 functional studies (knockout mouse models, MMR biochemistry) but none tested this exact nonsense variant or a systematically characterized range that includes codon 441. Details ▾Hide ▴
Evidence considered
- Six publications reviewed: all address PMS2 function at gene level
- none report experimental testing of c.1321G>T or p.Glu441Ter
- Functional-assay-SVI-documentation-MMR.xlsx does not list this variant
Still missing
- No variant-specific functional assay data (e.g.
- MMR activity
- protein expression
- splicing assay)
PP1 No cosegregation data is available for NM_000535.6:c.1321G>T. Cosegregation analysis requires pedigree data with combined Bayes Likelihood Ratio calculation; none was provided or identified in the case materials. Details ▾Hide ▴
Evidence considered
- No pedigree or cosegregation data identified in case materials
Still missing
- No cosegregation data available
PP4 No tumor-specific MSI or IHC data is available for NM_000535.6:c.1321G>T carriers in the case materials. PP4 requires at least one CRC/endometrial MSI-H tumor with loss of PMS2 protein expression consistent with the variant location, or tumor genome data. While the PMS2 gene is associated with Lynch syndrome and loss of MMR function is the established disease mechanism, variant-level tumor phenotype data is absent. Details ▾Hide ▴
Evidence considered
- OncoKB classifies variant as Likely Oncogenic / Likely Loss-of-function
- consistent with MMR deficiency mechanism
- No patient-level tumor MSI or IHC data provided in case evidence
Still missing
- No tumor MSI/IHC data for variant carriers
- if clinical data becomes available showing PMS2-deficient MSI-H tumors
- PP4 may be applicable
Sources
BA1 NM_000535.6:c.1321G>T is absent from gnomAD v4.1 (Grpmax filtering allele frequency = 0). The PMS2 VCEP BA1 threshold is ≥0.0028 (0.28%). This variant does not meet the stand-alone benign population frequency criterion. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 Grpmax FAF: absent (0 alleles)
- VCEP BA1 threshold: ≥0.0028 (0.28%)
Sources
BS1 NM_000535.6:c.1321G>T is absent from gnomAD v4.1. The PMS2 VCEP BS1 threshold is ≥0.00028 and <0.0028 (0.028-0.28%). This variant is absent, not within the BS1 range. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 Grpmax FAF: absent (0 alleles)
- VCEP BS1 threshold: 0.00028–0.0028
Sources
BS2 No evidence of co-occurrence in trans with a known pathogenic PMS2 variant in a patient with CRC after age 45 and no CMMRD features. BS2 requires confirmed phase (parental testing) showing trans configuration with a known pathogenic variant. Details ▾Hide ▴
Evidence considered
- No co-occurrence data identified in case materials or literature
Still missing
- No trans co-occurrence data available
BS3 No variant-specific functional data demonstrating proficient MMR function for NM_000535.6:c.1321G>T. The PMS2 VCEP BS3 requires calibrated functional assays with odds for pathogenicity ≤0.05, or variant-specific proficient function in protein/mRNA-based assays. No such data exists for this variant. Details ▾Hide ▴
Evidence considered
- No functional data identified demonstrating proficient (benign) MMR function for this variant
Still missing
- No functional assay data demonstrating normal MMR activity for this variant
BS4 No lack-of-cosegregation data is available. BS4 requires combined Bayes Likelihood Ratio <0.05 (Strong) or >0.05 and ≤0.48 (Supporting) from pedigree analysis. None was provided in the case materials. Details ▾Hide ▴
Evidence considered
- No pedigree or lack-of-cosegregation data identified
Still missing
- No cosegregation data available
BP5 No tumor data showing MSS and/or retained PMS2 protein expression in variant carriers is available. BP5 requires ≥2 CRC/endometrial tumors with MSS and/or no loss of MMR expression, or BRAF V600E/MLH1 methylation in MSI-H tumors. No such evidence exists in the case materials. Details ▾Hide ▴
Evidence considered
- No tumor MSS or discordant IHC data identified for variant carriers
Still missing
- No tumor phenotype data available to assess BP5
Not applicable · 17· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 in the PMS2 VCEP applies only to predicted missense substitutions encoding the same amino acid change as a previously established pathogenic variant. NM_000535.6:c.1321G>T is a nonsense variant (p.Glu441Ter), not a missense substitution. Details ▾Hide ▴
Sources
PS4 VCEPPS4 is marked Not Applicable by the InSiGHT PMS2 VCEP v2.0. Details ▾Hide ▴
Sources
PM1 VCEPPM1 is marked Not Applicable by the InSiGHT PMS2 VCEP v2.0. Details ▾Hide ▴
Sources
PM3 N/ASkipped per user instruction: trivially not applicable. Details ▾Hide ▴
No further detail was recorded.
PM4 VCEPSkipped per user instruction: trivially not applicable. Details ▾Hide ▴
No further detail was recorded.
PM5 N/APM5 in the PMS2 VCEP applies only to missense changes at an amino acid residue where a different missense change has been classified as Pathogenic/Likely Pathogenic. NM_000535.6:c.1321G>T is a nonsense variant (p.Glu441Ter) introducing a stop codon, not a missense change. The pm5_candidates.json confirms the variant is not missense-like. Details ▾Hide ▴
Sources
cspec ↗pm5_candidates
PM6 VCEPPM6 is marked Not Applicable by the InSiGHT PMS2 VCEP v2.0. Details ▾Hide ▴
Sources
PP2 VCEPPP2 is marked Not Applicable by the InSiGHT PMS2 VCEP v2.0. Details ▾Hide ▴
Sources
PP3 N/APP3 in the PMS2 VCEP applies only to missense variants with HCI MAPP/PP2 Prior P scores (>0.68 for Supporting, >0.81 for Moderate). This is a nonsense variant and HCI prior is not available. BayesDel score (0.297) is noted but does not trigger PP3 under the VCEP framework, which relies exclusively on the HCI prior calibration for in silico evidence. Details ▾Hide ▴
Evidence considered
- HCI prior not found for c.1321G>T (nonsense variant
- not in HCI table)
- BayesDel score: 0.297 (not used by VCEP framework)
- REVEL score: not found
Sources
PP5 VCEPPP5 is marked Not Applicable by the InSiGHT PMS2 VCEP v2.0. Details ▾Hide ▴
Sources
BP1 VCEPBP1 is marked Not Applicable by the InSiGHT PMS2 VCEP v2.0. Details ▾Hide ▴
Sources
BP2 VCEPBP2 is marked Not Applicable by the InSiGHT PMS2 VCEP v2.0. Details ▾Hide ▴
Sources
BP3 VCEPSkipped per user instruction: trivially not applicable. Details ▾Hide ▴
No further detail was recorded.
BP4 N/ABP4 in the PMS2 VCEP applies only to missense variants with HCI MAPP/PP2 Prior P score <0.11, or intronic/synonymous variants with SpliceAI delta ≤0.1. This is a nonsense variant. SpliceAI max delta is 0.03 (no splicing impact predicted) but the VCEP BP4 rule does not extend to nonsense variants. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta: 0.03 (no splicing impact)
- HCI prior: not found (nonsense variant)
Sources
BP6 VCEPBP6 is marked Not Applicable by the InSiGHT PMS2 VCEP v2.0. Details ▾Hide ▴
Sources
BP7 N/ABP7 in the PMS2 VCEP applies only to synonymous (silent) or intronic variants at or beyond -21/+7 positions. NM_000535.6:c.1321G>T is a nonsense variant producing a premature termination codon; BP7 is not applicable. Details ▾Hide ▴
Sources
PS5 N/APS5 is not defined in the InSiGHT PMS2 VCEP v2.0 framework. Under VCEP framework precedence, criteria not specified by the expert panel are not applied. Additionally, this is a nonsense variant, making the generic PS5 criterion (same amino acid change as established pathogenic variant by different nucleotide change) inapplicable. Details ▾Hide ▴
Sources
Identifiers
- Gene
- PMS2
- Transcript
- NM_000535.6
- Coding (HGVS c.)
- NM_000535.6:c.1321G>T
- Protein (HGVS p.)
- NP_000526.2:p.(Glu441Ter)
- GRCh38
- chr7:5987444 C>A
- GRCh37
- chr7:6027075 C>A
- ClinVar
- 1788497, 1769925, 819712
Gene diagram
Every interpreted variant in PMS2, mapped onto the exon structure of NM_000535.6. Select a row to find it on the plot.
PMS2NM_000535.6
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
- 0.297
How the predictions were used
PP3 N/APP3 in the PMS2 VCEP applies only to missense variants with HCI MAPP/PP2 Prior P scores (>0.68 for Supporting, >0.81 for Moderate). This is a nonsense variant and HCI prior is not available. BayesDel score (0.297) is noted but does not trigger PP3 under the VCEP framework, which relies exclusively on the HCI prior calibration for in silico evidence. Details ▾Hide ▴
Evidence considered
- HCI prior not found for c.1321G>T (nonsense variant
- not in HCI table)
- BayesDel score: 0.297 (not used by VCEP framework)
- REVEL score: not found
Sources
BP4 N/ABP4 in the PMS2 VCEP applies only to missense variants with HCI MAPP/PP2 Prior P score <0.11, or intronic/synonymous variants with SpliceAI delta ≤0.1. This is a nonsense variant. SpliceAI max delta is 0.03 (no splicing impact predicted) but the VCEP BP4 rule does not extend to nonsense variants. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta: 0.03 (no splicing impact)
- HCI prior: not found (nonsense variant)
Sources
BP7 N/ABP7 in the PMS2 VCEP applies only to synonymous (silent) or intronic variants at or beyond -21/+7 positions. NM_000535.6:c.1321G>T is a nonsense variant producing a premature termination codon; BP7 is not applicable. Details ▾Hide ▴
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). BayesDel score = 0.297099.
6 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
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.Describes PMS2 knockout mice as hypersensitive to MNU-induced thymic lymphoma. Examines carcinogen sensitivity in heterozygous PMS2-deficient mice. NM_000535.6:c.1321G>T was not identified in this paper.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.Compares mutation frequencies and spectra in Msh2-deficient versus Pms2-deficient mice using lacI, supF, and cII reporter genes. Msh2 deficiency produces higher mutation frequencies than Pms2 deficiency, with differing proportions of frameshifts and transversions. NM_000535.6:c.1321G>T was not identified.Does not name this variant
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PMID 12697830 ↗Dimerization of MLH1 and PMS2 limits nuclear localization of MutLalpha.Investigates MLH1 and PMS2 dimerization and its role in limiting nuclear localization of MutLalpha. Demonstrates that dimerization regulates MMR protein compartmentalization. NM_000535.6:c.1321G>T was not identified.Does not name this variant
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PMID 16144131 ↗Two PMS2 mutations in a Turcot syndrome family with small bowel cancers.Reports two different PMS2 mutations (1951C>T p.Q643X and 161C>T p.S46I) in a Turcot syndrome family with small bowel cancers and glioblastoma. Demonstrates PMS2 IHC loss in proband tumors. NM_000535.6:c.1321G>T (p.Glu441Ter) is not the variant reported.Does not name this variant
Quoted passage
two constitutional PMS2 mutations were identified: a truncating nonsense mutation in exon 11 (1951C>T; Q643X) and a missense mutation affecting exon 2 (161G>T; S46I)
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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.Reports PMS2 and MSH6 mutation spectrum in Australian Lynch syndrome families, with novel mutations, cancer risk estimates, and age of CRC diagnosis. NM_000535.6:c.1321G>T was not identified in the full text.Does not name this variant
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PMID 25394175 ↗A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.Hampel H et al. · 2015ACMG/NSGC practice guideline for referral indications for cancer predisposition assessment. Provides criteria for genetic counseling referral covering Lynch syndrome and other hereditary cancer syndromes. Does not mention any specific PMS2 variants.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 0.030
Open source ↗
ClinVar
1 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/1769925/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/7-6027075-C-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr7-5987444-C-A?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/7-5987444-C-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000535.6%3Ac.1321…
- OncoKB ↗www.oncokb.org/gene/PMS2/E441*
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=PMS2+c.1321G%3ET
- 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 (1 clinical laboratory). (ClinVarID = 1769925)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). BayesDel score = 0.297099.
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.