About PMS2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PMS2 c.1239del, p.(Asp414ThrfsTer34)
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 v2.0.0. 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
This frameshift variant is predicted to cause p.(Asp414ThrfsTer34) and introduce a premature termination codon well before codon 798 in PMS2. Under the PMS2 VCEP specification, nonsense or frameshift variants introducing a premature stop at or before codon 798 meet PVS1 at very strong strength.
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1 and gnomAD-Canada v1.0 and is present only once in gnomAD v4.1 (1/1613994 alleles; AF 6.19581e-07, 0.00006%), which is below the PMS2 VCEP PM2_Supporting threshold of 0.00002.
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 2.0.0 v2.0.0 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
1 / 1,613,994 alleles
gnomAD v4.1: 1 / 1,613,994 alleles. Recorded AF 6.19581e-07. Recorded homozygote count 0.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.020 maximum delta
Recorded SpliceAI maximum delta score: 0.020. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
6 reported laboratory submissions
6 Pathogenic.
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
27 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV56220545, n = 27 times).
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: 2 met · 2 not met · 9 not assessed · 15 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
The PMS2 NM_000535.7:c.1239del (p.(Asp414ThrfsTer34), p.(D414Tfs*34)) variant has been reported in ClinVar as Pathogenic by 6 clinical laboratories.
This variant is absent from gnomAD v2.1 and gnomAD-Canada v1.0 and is present only once in gnomAD v4.1 (AF 6.19581e-07; 1/1613994 alleles), which is below the PMS2 PM2_Supporting threshold of 0.00002.
This frameshift is predicted to introduce a premature termination codon after 34 altered amino acids, and the PMS2 VCEP specification applies PVS1 at very strong strength to frameshift variants with a premature stop at or before codon 798.
SpliceAI predicts no significant splice impact for this variant (maximum delta score 0.02); however, the primary predicted effect remains a truncating frameshift rather than an isolated splice or missense change.
No criteria match.
Met · 2
PVS1 Very strongThis frameshift variant is predicted to cause p.(Asp414ThrfsTer34) and introduce a premature termination codon well before codon 798 in PMS2. Under the PMS2 VCEP specification, nonsense or frameshift variants introducing a premature stop at or before codon 798 meet PVS1 at very strong strength. Details ▾Hide ▴
Rule
PMS2 VCEP PVS1_Very Strong for nonsense/frameshift variants introducing a premature termination codon <= codon 798.
Evidence considered
- Predicted frameshift consequence p.(Asp414ThrfsTer34)/p.(D414Tfs*34)
- PMS2 VCEP PVS1 rule for frameshift variants with premature stop codon at or before codon 798
Sources
PM2 SupportingThis variant is absent from gnomAD v2.1 and gnomAD-Canada v1.0 and is present only once in gnomAD v4.1 (1/1613994 alleles; AF 6.19581e-07, 0.00006%), which is below the PMS2 VCEP PM2_Supporting threshold of 0.00002. Details ▾Hide ▴
Rule
PMS2 VCEP PM2_Supporting for absent/extremely rare allele frequency < 0.00002 in gnomAD v4.
Evidence considered
- gnomAD v2.1 absent
- gnomAD v4.1 AF 6.19581e-07
- gnomAD-Canada absent
- PMS2 VCEP PM2 threshold
Sources
Not met · 2 · evaluated, threshold not reached
BA1 Population frequency does not meet BA1. The highest available gnomAD v4.1 frequency is 6.19581e-07 overall (0.00006%; 1/1613994 alleles), which is far below the PMS2 BA1 threshold of 0.0028. Details ▾Hide ▴
Rule
PMS2 VCEP BA1 requires gnomAD v4 grpmax filtering AF >= 0.0028.
Evidence considered
- gnomAD v4.1 AF 6.19581e-07
- PMS2 VCEP BA1 threshold 0.0028
Sources
BS1 Population frequency does not meet BS1. The highest available gnomAD v4.1 frequency is 6.19581e-07 overall (0.00006%; 1/1613994 alleles), which is below the PMS2 BS1 threshold of 0.00028. Details ▾Hide ▴
Rule
PMS2 VCEP BS1 requires gnomAD v4 grpmax filtering AF >= 0.00028 and < 0.0028.
Evidence considered
- gnomAD v4.1 AF 6.19581e-07
- PMS2 VCEP BS1 threshold 0.00028
Sources
Not assessed · 9 · no assessment recorded
PS2 No confirmed de novo occurrence data were identified for this variant, so PS2 cannot be applied. Details ▾Hide ▴
Evidence considered
- ClinVar exact-match record reviewed for case-level leads
Still missing
- Confirmed maternity/paternity data and phenotype-consistent de novo case evidence were not available.
Sources
PS3 Available evidence supports a truncating loss-of-function interpretation, but no variant-specific calibrated functional assay result or qualifying RNA study was identified to support PS3 under the PMS2 VCEP rules. Details ▾Hide ▴
Evidence considered
- Curated literature gateway identified functional context for PMS2 loss of function
- PMS2 VCEP PS3 rule requirements
Still missing
- No qualifying variant-specific functional assay or qualifying RNA study was available.
Sources
PM3 No confirmed in trans observation with another pathogenic or likely pathogenic PMS2 variant was identified for this variant, so PM3 cannot be applied. Details ▾Hide ▴
PP1 No segregation data were identified for this variant, so PP1 cannot be applied. Details ▾Hide ▴
PP4 No qualifying tumor MSI or mismatch repair immunohistochemistry data linked to this variant were identified, so PP4 cannot be applied. Details ▾Hide ▴
BS2 No evidence was identified showing this variant in trans with a known pathogenic PMS2 variant in an older individual without features of constitutional mismatch repair deficiency, so BS2 cannot be applied. Details ▾Hide ▴
Evidence considered
- PMS2 VCEP BS2 rule
Still missing
- No confirmed phase information and no qualifying clinical context for BS2 were available.
Sources
BS3 No variant-specific functional evidence demonstrating retained PMS2 function or normal RNA behavior was identified, so BS3 cannot be applied. Details ▾Hide ▴
Evidence considered
- Curated literature gateway reviewed for functional evidence
- PMS2 VCEP BS3 rule requirements
Still missing
- No qualifying benign functional or RNA assay evidence was available.
Sources
BS4 No lack-of-segregation data were identified for this variant, so BS4 cannot be applied. Details ▾Hide ▴
BP5 No qualifying tumor findings inconsistent with PMS2-related disease were identified, so BP5 cannot be applied. Details ▾Hide ▴
Evidence considered
- PMS2 VCEP BP5 tumor-based rule
Still missing
- No qualifying MSS
- retained-protein
- or gene-inconsistent tumor evidence was available.
Sources
Not applicable · 15· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/AThis criterion is not applicable because the variant is a frameshift deletion rather than a missense change or a non-canonical splice variant evaluated under the PMS2 PS1 rule. Details ▾Hide ▴
PS4 VCEPThis criterion is not applicable in the PMS2 VCEP specification. Details ▾Hide ▴
PM1 VCEPThis criterion is not applicable in the PMS2 VCEP specification. Details ▾Hide ▴
PM4 VCEPThis criterion is not applicable in the PMS2 VCEP specification. Details ▾Hide ▴
PM5 N/AThis criterion is not applicable because the PMS2 PM5 rule is for same-residue missense substitutions, and this variant is a frameshift deletion. Details ▾Hide ▴
Evidence considered
- PM5 comparator review showed non-missense variant is not eligible
Sources
cspec ↗pm5_candidates
PM6 VCEPThis criterion is not applicable in the PMS2 VCEP specification. Details ▾Hide ▴
PP2 VCEPThis criterion is not applicable in the PMS2 VCEP specification. Details ▾Hide ▴
PP3 N/AThis criterion is not applicable because the PMS2 PP3 rule is for missense substitutions with HCI prior support or non-canonical splice variants with SpliceAI support, and this variant is a frameshift deletion. SpliceAI shows a low maximum delta score of 0.02, but that does not convert this frameshift into a PP3-eligible variant class. Details ▾Hide ▴
Evidence considered
- Variant consequence is frameshift
- SpliceAI max delta score 0.02
Sources
PP5 VCEPThis criterion is not applicable in the PMS2 VCEP specification. Details ▾Hide ▴
BP1 VCEPThis criterion is not applicable in the PMS2 VCEP specification. Details ▾Hide ▴
BP2 VCEPThis criterion is not applicable in the PMS2 VCEP specification. Details ▾Hide ▴
BP3 VCEPThis criterion is not applicable in the PMS2 VCEP specification. Details ▾Hide ▴
BP4 N/AThis criterion is not applicable because the PMS2 BP4 rule is limited to missense variants with HCI prior less than 0.11 or to synonymous/intronic variants with SpliceAI less than or equal to 0.1, and this variant is a frameshift deletion. Although SpliceAI predicts no significant splice impact (max delta score 0.02), that does not satisfy BP4 for this variant class. Details ▾Hide ▴
Evidence considered
- Variant consequence is frameshift
- SpliceAI max delta score 0.02
Sources
BP6 VCEPThis criterion is not applicable in the PMS2 VCEP specification. Details ▾Hide ▴
BP7 N/AThis criterion is not applicable because the variant is not synonymous and is not an intronic change at a BP7-eligible position. Details ▾Hide ▴
Identifiers
- Gene
- PMS2
- Transcript
- NM_000535.7
- Coding (HGVS c.)
- NM_000535.7:c.1239del
- Protein (HGVS p.)
- NP_000526.2:p.(Asp414ThrfsTer34)
- GRCh38
- chr7:5987525 CT>C
- GRCh37
- chr7:6027156 CT>C
- ClinVar
- 2842038, 1171824
- COSMIC
- COSV56220545
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
1 / 1,613,994 alleles
AF 6.2e-07 · 0 homozygotes
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 6.2e-07 · 1 / 1,613,994 alleles · 0 hom
| European (non-Finnish)1 / 1,179,966 | 8.5e-07 |
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 6.19581e-07; MAF= 0.00006%, 1/1613994 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47482e-07; MAF= 0.00008%, 1/1179966 alleles, homozygotes = 0).
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 N/AThis criterion is not applicable because the PMS2 PP3 rule is for missense substitutions with HCI prior support or non-canonical splice variants with SpliceAI support, and this variant is a frameshift deletion. SpliceAI shows a low maximum delta score of 0.02, but that does not convert this frameshift into a PP3-eligible variant class. Details ▾Hide ▴
Evidence considered
- Variant consequence is frameshift
- SpliceAI max delta score 0.02
Sources
BP4 N/AThis criterion is not applicable because the PMS2 BP4 rule is limited to missense variants with HCI prior less than 0.11 or to synonymous/intronic variants with SpliceAI less than or equal to 0.1, and this variant is a frameshift deletion. Although SpliceAI predicts no significant splice impact (max delta score 0.02), that does not satisfy BP4 for this variant class. Details ▾Hide ▴
Evidence considered
- Variant consequence is frameshift
- SpliceAI max delta score 0.02
Sources
BP7 N/AThis criterion is not applicable because the variant is not synonymous and is not an intronic change at a BP7-eligible position. Details ▾Hide ▴
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).
9 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 12697830 ↗Dimerization of MLH1 and PMS2 limits nuclear localization of MutLalpha.No paper-specific finding is recorded.
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PMID 21376568 ↗Paediatric intestinal cancer and polyposis due to bi-allelic PMS2 mutations: case series, review and follow-up guidelines.Herkert JC et al. · 2011No paper-specific finding is recorded.
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PMID 24362816 ↗Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database.Thompson BA et al. · 2014No paper-specific finding is recorded.
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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.No paper-specific finding is recorded.
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PMID 10874005 ↗Mutagenesis in PMS2- and MSH2-deficient mice indicates differential protection from transversions and frameshifts.No paper-specific finding is recorded.
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PMID 16144131 ↗Two PMS2 mutations in a Turcot syndrome family with small bowel cancers.No paper-specific finding is recorded.
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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.No paper-specific finding is recorded.
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PMID 23619274 ↗American College of Medical Genetics and Genomics technical standards and guidelines: microarray analysis for chromosome abnormalities in neoplastic disorders.No paper-specific finding is recorded.
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PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.No paper-specific finding is recorded.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
1 / 1,613,994 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.020
Open source ↗
ClinVar
6 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/1171824/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/7-6027156-CT-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr7-5987525-CT-C?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/7-5987525-CT-C
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000535.7%3Ac.1239…
- OncoKB ↗www.oncokb.org/gene/PMS2/D414Tfs*34
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=125055697
- 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
This variant is present in gnomAD v4.1 (AF= 6.19581e-07; MAF= 0.00006%, 1/1613994 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47482e-07; MAF= 0.00008%, 1/1179966 alleles, homozygotes = 0).
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 (6 clinical laboratories). (ClinVarID = 1171824)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).
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 previously been reported in somatic cancers (COSMIC; COSV56220545, n = 27 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.