About PMS2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PMS2 c.2096A>T, p.(Asp699Val)
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
PM2Supporting
PM2 · supporting
The variant is absent from gnomAD v4.1, meeting the VCEP PM2_Supporting threshold of allele frequency <0.00002 (<1 in 50,000 alleles).
PP3Moderate
PP3 · moderate
HCI MAPP/PP2 Prior probability for c.2096A>T (p.D699V) is 0.8907, which exceeds the VCEP PP3_Moderate threshold of >0.81.
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: PM2 supporting, PP3 moderate; 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
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. PMS2, an endonuclease involved in DNA repair, is altered in various cancers.
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.
29 criteria with recorded statuses: 2 met · 7 not met · 7 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
PM2_Supporting is met: the variant is absent from gnomAD v4.1, meeting the VCEP threshold of <0.00002 allele frequency.
PP3_Moderate is met: the HCI MAPP/PP2 Prior probability for p.Asp699Val is 0.8907, exceeding the VCEP PP3_Moderate threshold of >0.81.
Multiple criteria could not be assessed due to absence of variant-specific data: PS3 (functional assays), PP1 (co-segregation), PP4 (tumor phenotype), BS2 (co-occurrence in trans), BS3 (benign functional evidence), BS4 (lack of co-segregation), and BP5 (tumor MSS/IHC data).
The variant has not been observed in population databases and is predicted damaging by multiple in silico tools (REVEL 0.969, BayesDel 0.419), but no clinical case reports, tumor data, or functional studies have been identified to further support or refute pathogenicity.
No criteria match.
Met · 2
PM2 SupportingThe variant is absent from gnomAD v4.1, meeting the VCEP PM2_Supporting threshold of allele frequency <0.00002 (<1 in 50,000 alleles). Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v4.1 (AF = 0)
- Absent from gnomAD v2.1
- Absent from gnomAD-Canada v1.0
Sources
PP3 ModerateHCI MAPP/PP2 Prior probability for c.2096A>T (p.D699V) is 0.8907, which exceeds the VCEP PP3_Moderate threshold of >0.81. Details ▾Hide ▴
Evidence considered
- HCI prior probability = 0.8907
- MAPP score = 22.25
- Custom PP2 score = 0.999
- REVEL score = 0.969 (consistent with pathogenic prediction)
Sources
Not met · 7 · evaluated, threshold not reached
PS1 No alternative nucleotide change at codon 699 producing p.(Asp699Val) has been established as Pathogenic by this VCEP. The only single-nucleotide variant producing Asp699Val is c.2096A>T itself. Details ▾Hide ▴
Evidence considered
- HCI priors database confirms c.2096A>T is the only nucleotide substitution at codon 699 producing p.D699V
Sources
cspec ↗vcep_hci_priors_pms2
PS2 No de novo occurrence data are available for this variant. PS2 requires at least 0.5 de novo points per the VCEP framework. Details ▾Hide ▴
Evidence considered
- No de novo observations identified in ClinVar
- literature
- or database evidence
Still missing
- No parental testing data available
Sources
PM5 No different missense variant at amino acid residue Asp699 has been classified as Pathogenic or Likely Pathogenic by this VCEP. PM5 requires a known P/LP missense change at the same residue. Details ▾Hide ▴
Evidence considered
- VCEP pilot variants spreadsheet scanned
- no P/LP missense at codon 699 identified
- ClinVar PM5 search found 0 eligible same-residue comparator candidates
Sources
BA1 The variant is absent from gnomAD v4 and does not meet the VCEP BA1 threshold of Grpmax filtering allele frequency ≥0.0028 (0.28%). Details ▾Hide ▴
BS1 The variant is absent from gnomAD v4 and does not meet the VCEP BS1 threshold of Grpmax filtering allele frequency ≥0.00028 (0.028%). Details ▾Hide ▴
BP4 HCI MAPP/PP2 Prior probability for this missense variant is 0.8907, which does not meet the VCEP BP4_Supporting threshold of <0.11. SpliceAI delta score is 0.00, but the SpliceAI-based BP4 rule applies only to intronic and synonymous variants per the VCEP specification. Details ▾Hide ▴
Evidence considered
- HCI prior = 0.8907 (not <0.11)
- SpliceAI max delta = 0.00 (BP4 for synonymous/intronic only per VCEP)
- REVEL = 0.969 (pathogenic prediction)
- BayesDel = 0.419 (intermediate)
Sources
BP7 BP7 applies only to synonymous (silent) or intronic variants at or beyond -21/+7 per the VCEP specification. c.2096A>T is a missense variant (p.Asp699Val) and does not qualify. Details ▾Hide ▴
Not assessed · 7 · no assessment recorded
PS3 No variant-specific functional assay data were identified for c.2096A>T in the VCEP functional assay documentation (Functional-assay-SVI-documentation-MMR.xlsx) or in published literature. Details ▾Hide ▴
Evidence considered
- VCEP functional assay spreadsheet scanned
- no entry for p.D699V or codon 699 found
Still missing
- No variant-specific MMR functional assay data (e.g.
- complementation assay
- in vitro MMR activity
- protein expression/stability) available in current evidence
Sources
vcep_functional_assay_svi_documentation_mmr
PP1 No co-segregation data are available for this variant. Details ▾Hide ▴
Evidence considered
- No family segregation data identified in ClinVar submissions or published literature
Still missing
- No pedigrees or co-segregation analysis available
Sources
PP4 No MSI or immunohistochemistry tumor data are available for patients carrying this variant. PP4 requires MSI-H tumors and/or loss of MMR protein expression consistent with PMS2. Details ▾Hide ▴
Evidence considered
- No tumor phenotype data available for variant carriers
Still missing
- No MSI testing results
- No PMS2 IHC data from variant carriers
Sources
BS2 No data are available regarding co-occurrence in trans with a known pathogenic PMS2 variant in a patient with colorectal cancer after age 45 without CMMRD features. Details ▾Hide ▴
Evidence considered
- No co-occurrence in trans data identified
Still missing
- No phase-confirmed co-occurrence data with known pathogenic PMS2 variants
Sources
BS3 No variant-specific functional assay data demonstrating proficient MMR function are available for c.2096A>T. Details ▾Hide ▴
Evidence considered
- VCEP functional assay spreadsheet scanned
- no entry for p.D699V found
Still missing
- No functional evidence of normal MMR activity for this variant
Sources
vcep_functional_assay_svi_documentation_mmrvcep_functional_assay_flowchart
BS4 No segregation data are available to assess lack of co-segregation with disease. Details ▾Hide ▴
Evidence considered
- No family segregation data available
Still missing
- No pedigree data for co-segregation analysis
Sources
BP5 No tumor MSI or IHC data are available to assess whether tumors are MSS or show preserved MMR protein expression inconsistent with PMS2 pathogenicity. Details ▾Hide ▴
Evidence considered
- No tumor phenotype data available
Still missing
- No MSI status data
- No IHC data for MMR proteins in tumors from variant carriers
Sources
Not applicable · 13· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 is not applicable: this is a missense substitution variant, not a null variant (nonsense, frameshift, or canonical ±1,2 splice site) per the PMS2 VCEP PVS1 rules. Details ▾Hide ▴
Evidence considered
- Missense substitution does not meet VCEP PVS1 null-variant criteria
Sources
PS4 VCEPVCEP designates PS4 as Not Applicable for PMS2. Details ▾Hide ▴
Sources
PM1 VCEPVCEP designates PM1 as Not Applicable for PMS2. Details ▾Hide ▴
Sources
PM3 N/ASkipped per instruction. Details ▾Hide ▴
No further detail was recorded.
PM4 VCEPSkipped per instruction. Details ▾Hide ▴
No further detail was recorded.
PM6 VCEPVCEP designates PM6 as Not Applicable for PMS2. Details ▾Hide ▴
Sources
PP2 VCEPVCEP designates PP2 as Not Applicable for PMS2. Details ▾Hide ▴
Sources
PP5 VCEPVCEP designates PP5 as Not Applicable for PMS2. Details ▾Hide ▴
Sources
BP1 VCEPVCEP designates BP1 as Not Applicable for PMS2. Details ▾Hide ▴
Sources
BP2 VCEPVCEP designates BP2 as Not Applicable for PMS2. Details ▾Hide ▴
Sources
BP3 VCEPSkipped per instruction. VCEP designates BP3 as Not Applicable. Details ▾Hide ▴
Sources
BP6 VCEPVCEP designates BP6 as Not Applicable for PMS2. Details ▾Hide ▴
Sources
PS5 N/AVCEP designates PS5 as Not Applicable for PMS2. Details ▾Hide ▴
Sources
Identifiers
- Gene
- PMS2
- Transcript
- NM_000535.7
- Coding (HGVS c.)
- NM_000535.7:c.2096A>T
- Protein (HGVS p.)
- NP_000526.2:p.(Asp699Val)
- GRCh38
- chr7:5982902 T>A
- GRCh37
- chr7:6022533 T>A
- ClinVar
- 4710963, 3890972
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
- 0.969
- BayesDel
- 0.419
How the predictions were used
PP3 ModerateHCI MAPP/PP2 Prior probability for c.2096A>T (p.D699V) is 0.8907, which exceeds the VCEP PP3_Moderate threshold of >0.81. Details ▾Hide ▴
Evidence considered
- HCI prior probability = 0.8907
- MAPP score = 22.25
- Custom PP2 score = 0.999
- REVEL score = 0.969 (consistent with pathogenic prediction)
Sources
BP4 HCI MAPP/PP2 Prior probability for this missense variant is 0.8907, which does not meet the VCEP BP4_Supporting threshold of <0.11. SpliceAI delta score is 0.00, but the SpliceAI-based BP4 rule applies only to intronic and synonymous variants per the VCEP specification. Details ▾Hide ▴
Evidence considered
- HCI prior = 0.8907 (not <0.11)
- SpliceAI max delta = 0.00 (BP4 for synonymous/intronic only per VCEP)
- REVEL = 0.969 (pathogenic prediction)
- BayesDel = 0.419 (intermediate)
Sources
BP7 BP7 applies only to synonymous (silent) or intronic variants at or beyond -21/+7 per the VCEP specification. c.2096A>T is a missense variant (p.Asp699Val) and does not qualify. Details ▾Hide ▴
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.969. BayesDel score = 0.419018. HCI prior probability for pathogenicity = 0.8907. MAPP score = 22.25. Custom PP2 score = 0.999.
1 paper record 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
-
PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.Nykamp K et al. · 2017Describes the Sherloc framework for refining ACMG-AMP variant classification criteria. NM_000535.7:c.2096A>T was not identified 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 0.000
Open source ↗
ClinVar
Captured ClinVar source record
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/?term=NM_000535.7%3Ac.2096A%3ET
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/7-6022533-T-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr7-5982902-T-A?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/7-5982902-T-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000535.7%3Ac.2096…
- OncoKB ↗www.oncokb.org/gene/PMS2/D699V
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=PMS2+c.2096A%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 is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.969. BayesDel score = 0.419018. HCI prior probability for pathogenicity = 0.8907. MAPP score = 22.25. Custom PP2 score = 0.999.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. PMS2, an endonuclease involved in DNA repair, is altered in various cancers.
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.