About PMS2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PMS2 c.33T>C, p.(Pro11=)
Classification
Not classified
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. Select a step to read what it means.
Not classified yet.Select a step to read what it means.
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: 1
Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
NM_000535.7:c.33T>C is absent from gnomAD v4.1 (0 alleles), meeting the InSiGHT VCEP PM2_Supporting threshold of allele frequency < 0.00002 (<1 in 50,000 alleles).
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
NM_000535.7:c.33T>C is a synonymous variant and SpliceAI predicts no splicing impact (max delta score = 0.00, which is ≤ 0.1), meeting the InSiGHT VCEP BP4_Supporting threshold for intronic and synonymous variants.
Recorded classification: Not classified
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 Rule31 (Benign.Supporting >=1 + Pathogenic.Supporting >=1) with applied criteria: PM2 supporting, BP4 supporting; maps to Uncertain Significance - Conflicting Evidence.
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
4 reported laboratory submissions
2 Likely benign · 1 Likely Benign · 1 Benign. ClinVar API review status: criteria provided, multiple submitters, no conflicts.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
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.
26 criteria with recorded statuses: 2 met · 6 not met · 6 not assessed · 12 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.33T>C (p.Pro11=) is a synonymous variant in exon 2 of PMS2. It is absent from gnomAD v4.1, meeting PM2_Supporting under the InSiGHT VCEP v2.0.0 framework (allele frequency < 0.00002).
SpliceAI predicts no splicing impact for this synonymous variant (max delta score = 0.00, ≤ 0.1), meeting BP4_Supporting under the InSiGHT VCEP v2.0.0 framework.
ClinVar records this variant as Likely benign (4 submissions from clinical laboratories; ClinVar Variation ID 525878), though the review status is criteria provided, single submitter and this alone does not constitute an independent ACMG criterion under the VCEP framework.
No functional studies, segregation data, tumor phenotype data, or variant-specific literature were identified for NM_000535.7:c.33T>C. Multiple criteria (PS3, BS3, PP1, PP4, BS4, BP5) could not be assessed due to absence of evidence.
Applying the InSiGHT MMR VCEP v2.0.0 combination rules: PM2_Supporting (pathogenic supporting) and BP4_Supporting (benign supporting) are both met. With one pathogenic supporting and one benign supporting criterion and no criteria at higher strength levels, the combination rules do not yield a definitive classification. This results in a classification of Uncertain Significance.
No criteria match.
Met · 2
PM2 SupportingNM_000535.7:c.33T>C is absent from gnomAD v4.1 (0 alleles), meeting the InSiGHT VCEP PM2_Supporting threshold of allele frequency < 0.00002 (<1 in 50,000 alleles). Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v4.1 (0/1
- 614
- 074 alleles
- AF < 0.00002). Also absent from gnomAD v2.1 and gnomAD-Canada.
Sources
BP4 SupportingNM_000535.7:c.33T>C is a synonymous variant and SpliceAI predicts no splicing impact (max delta score = 0.00, which is ≤ 0.1), meeting the InSiGHT VCEP BP4_Supporting threshold for intronic and synonymous variants. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score = 0.00. Synonymous variant with no predicted effect on splicing.
Sources
Not met · 6 · evaluated, threshold not reached
PS2 No de novo observations reported for NM_000535.7:c.33T>C. De novo scoring (0 points) does not meet any PS2 strength threshold under the InSiGHT MMR VCEP v2.0.0 framework. Details ▾Hide ▴
Evidence considered
- No de novo cases identified in ClinVar submissions
- literature
- or databases.
PP3 PP3 under the InSiGHT VCEP requires either a missense variant with HCI prior probability > 0.68, or a predicted splice defect at non-canonical splice nucleotides with SpliceAI delta ≥ 0.2. NM_000535.7:c.33T>C is a synonymous variant not represented in the HCI prior table, and SpliceAI predicts no splicing impact (max delta = 0.00). Neither pathway is satisfied. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score = 0.00 (no predicted splicing impact). HCI prior not available for this synonymous variant.
Sources
BA1 BA1 requires gnomAD v4 Grpmax filtering allele frequency ≥ 0.0028 (0.28%). NM_000535.7:c.33T>C is absent from gnomAD v4.1 and does not meet this threshold. Details ▾Hide ▴
BS1 BS1 requires gnomAD v4 Grpmax filtering allele frequency ≥ 0.00028 and < 0.0028. NM_000535.7:c.33T>C is absent from gnomAD v4.1 and does not meet this threshold. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v4.1 (0 alleles
- AF below BS1 threshold of 0.00028).
Sources
BS2 BS2 requires co-occurrence in trans with a known pathogenic PMS2 variant in a patient with colorectal cancer after age 45 without CMMRD. No such co-occurrence has been reported for NM_000535.7:c.33T>C. Details ▾Hide ▴
Evidence considered
- No co-occurrence observations in trans with a pathogenic PMS2 variant reported in ClinVar or literature.
BP7 BP7 requires a synonymous variant at or within -21/+7 of the exon-intron boundaries (splice consensus region). NM_000535.7:c.33T>C is located at cDNA position 33, which is nucleotide +10 of exon 2 (exon 2 spans c.24 to c.163). Position +10 is beyond the +7 boundary from the 5' splice acceptor site and does not satisfy BP7. Details ▾Hide ▴
Evidence considered
- c.33T>C is at nucleotide +10 of exon 2
- beyond the +7 splice consensus boundary.
Not assessed · 6 · no assessment recorded
PS3 No calibrated functional assay data or MMR functional assay results are available for NM_000535.7:c.33T>C. Functional assessment cannot be performed without variant-specific experimental evidence. Details ▾Hide ▴
Evidence considered
- No functional assay data identified in VCEP functional assay spreadsheet or literature.
Still missing
- No functional studies have been performed on this variant.
PP1 No co-segregation data are available for NM_000535.7:c.33T>C. Co-segregation analysis with Bayes Likelihood Ratio cannot be performed. Details ▾Hide ▴
Evidence considered
- No segregation data identified in ClinVar submissions or literature.
Still missing
- No family segregation studies available.
PP4 No tumor MSI/IHC data are available for patients carrying NM_000535.7:c.33T>C. PP4 requires CRC/endometrial MSI-H tumors with MMR protein expression loss consistent with variant location. Details ▾Hide ▴
Evidence considered
- No tumor phenotype data available in ClinVar submissions or literature.
Still missing
- No MSI or IHC data available for carriers of this variant.
BS3 No calibrated functional assay data demonstrating proficient MMR function are available for NM_000535.7:c.33T>C. BS3 cannot be assessed without variant-specific functional evidence. Details ▾Hide ▴
Evidence considered
- No functional assay data for this variant in VCEP functional assay spreadsheet or literature.
Still missing
- No functional studies demonstrating normal MMR function for this variant.
BS4 No segregation data are available to assess lack of co-segregation with disease for NM_000535.7:c.33T>C. Details ▾Hide ▴
Evidence considered
- No segregation data available.
Still missing
- No family segregation data for BS4 analysis.
BP5 No tumor MSS/IHC data are available for patients carrying NM_000535.7:c.33T>C. BP5 requires CRC/endometrial tumors with MSS and/or no loss of MMR protein expression. Details ▾Hide ▴
Evidence considered
- No tumor phenotype data available in ClinVar submissions or literature.
Still missing
- No MSS or IHC data for carriers of this variant.
Not applicable · 12· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ASynonymous variant (p.Pro11=) does not introduce a premature termination codon, is not at a canonical splice site, and does not fit any PVS1 null-variant bucket in the InSiGHT MMR VCEP v2.0.0 framework. Details ▾Hide ▴
No further detail was recorded.
PS1 N/APS1 requires a missense substitution encoding the same amino acid change as a known pathogenic variant, or a variant affecting a non-canonical splice nucleotide matching a pathogenic splice variant. This is a synonymous variant (p.Pro11=) encoding no amino acid change and is not at a splice nucleotide. Details ▾Hide ▴
No further detail was recorded.
PS4 VCEPPS4 is explicitly marked as Not Applicable by the InSiGHT MMR VCEP v2.0.0 framework for PMS2 variant classification. Details ▾Hide ▴
Evidence considered
- VCEP determination: PS4 not used in PMS2 classification framework.
Sources
PM1 VCEPPM1 is explicitly marked as Not Applicable by the InSiGHT MMR VCEP v2.0.0 framework for PMS2 variant classification. Details ▾Hide ▴
Evidence considered
- VCEP determination: PM1 not used in PMS2 classification framework.
Sources
PM5 N/APM5 requires a missense change at an amino acid residue where a different missense change is classified as Pathogenic or Likely Pathogenic. NM_000535.7:c.33T>C is a synonymous variant (p.Pro11=) and does not alter the amino acid. Details ▾Hide ▴
No further detail was recorded.
PM6 VCEPPM6 is explicitly marked as Not Applicable by the InSiGHT MMR VCEP v2.0.0 framework for PMS2 variant classification. Details ▾Hide ▴
Evidence considered
- VCEP determination: PM6 not used in PMS2 classification framework.
Sources
PP2 VCEPPP2 is explicitly marked as Not Applicable by the InSiGHT MMR VCEP v2.0.0 framework for PMS2 variant classification. Details ▾Hide ▴
Evidence considered
- VCEP determination: PP2 not used in PMS2 classification framework.
Sources
PP5 VCEPPP5 is explicitly marked as Not Applicable by the InSiGHT MMR VCEP v2.0.0 framework for PMS2 variant classification. Details ▾Hide ▴
Evidence considered
- VCEP determination: PP5 not used in PMS2 classification framework.
Sources
BP1 VCEPBP1 is explicitly marked as Not Applicable by the InSiGHT MMR VCEP v2.0.0 framework for PMS2 variant classification. Details ▾Hide ▴
Evidence considered
- VCEP determination: BP1 not used in PMS2 classification framework.
Sources
BP2 VCEPBP2 is explicitly marked as Not Applicable by the InSiGHT MMR VCEP v2.0.0 framework for PMS2 variant classification. Details ▾Hide ▴
Evidence considered
- VCEP determination: BP2 not used in PMS2 classification framework.
Sources
BP6 VCEPBP6 is explicitly marked as Not Applicable by the InSiGHT MMR VCEP v2.0.0 framework for PMS2 variant classification. Details ▾Hide ▴
Evidence considered
- VCEP determination: BP6 not used in PMS2 classification framework.
Sources
PS5 N/APS5 is not included in the InSiGHT MMR VCEP v2.0.0 criteria set for PMS2 and is not used in this framework. Details ▾Hide ▴
Evidence considered
- VCEP determination: PS5 not included in PMS2 classification framework.
Sources
Identifiers
- Gene
- PMS2
- Transcript
- NM_000535.7
- Coding (HGVS c.)
- NM_000535.7:c.33T>C
- Protein (HGVS p.)
- NP_000526.2:p.(Pro11=)
- GRCh38
- chr7:6006022 A>G
- GRCh37
- chr7:6045653 A>G
- ClinVar
- 1767741, 525878
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
BP4 SupportingNM_000535.7:c.33T>C is a synonymous variant and SpliceAI predicts no splicing impact (max delta score = 0.00, which is ≤ 0.1), meeting the InSiGHT VCEP BP4_Supporting threshold for intronic and synonymous variants. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score = 0.00. Synonymous variant with no predicted effect on splicing.
Sources
PP3 PP3 under the InSiGHT VCEP requires either a missense variant with HCI prior probability > 0.68, or a predicted splice defect at non-canonical splice nucleotides with SpliceAI delta ≥ 0.2. NM_000535.7:c.33T>C is a synonymous variant not represented in the HCI prior table, and SpliceAI predicts no splicing impact (max delta = 0.00). Neither pathway is satisfied. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score = 0.00 (no predicted splicing impact). HCI prior not available for this synonymous variant.
Sources
BP7 BP7 requires a synonymous variant at or within -21/+7 of the exon-intron boundaries (splice consensus region). NM_000535.7:c.33T>C is located at cDNA position 33, which is nucleotide +10 of exon 2 (exon 2 spans c.24 to c.163). Position +10 is beyond the +7 boundary from the 5' splice acceptor site and does not satisfy BP7. Details ▾Hide ▴
Evidence considered
- c.33T>C is at nucleotide +10 of exon 2
- beyond the +7 splice consensus boundary.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
7 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 25741868 ↗Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.Standards and guidelines for the interpretation of sequence variants (ACMG/AMP 2015 consensus recommendation). NM_000535.7:c.33T>C was not identified in this paper.Does not name this variant
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PMID 24493721 ↗American Society of Clinical Oncology Expert Statement: collection and use of a cancer family history for oncology providers.ASCO expert statement on collection and use of cancer family history for oncology providers. NM_000535.7:c.33T>C was not identified in this paper.Does not name this variant
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PMID 25711197 ↗Lynch Syndrome: A Primer for Urologists and Panel Recommendations.Review of Lynch syndrome for urologists with panel recommendations. NM_000535.7:c.33T>C was not identified in this paper.Does not name this variant
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PMID 26389210 ↗Genetics of Breast and Gynecologic Cancers (PDQ®): Health Professional Version.PDQ summary on genetics of breast and gynecologic cancers. NM_000535.7:c.33T>C was not identified in this paper.Does not name this variant
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PMID 34012068 ↗ACMG SF v3.0 list for reporting of secondary findings in clinical exome and genome sequencing: a policy statement of the American College of Medical Genetics and Genomics (ACMG).Miller DT et al. · 2021ACMG SF v3.0 list for reporting of secondary findings in clinical exome and genome sequencing. NM_000535.7:c.33T>C was not identified in this paper.Does not name this variant
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PMID 34043773 ↗European guidelines from the EHTG and ESCP for Lynch syndrome: an updated third edition of the Mallorca guidelines based on gene and gender.Seppälä TT et al. · 2021European guidelines from EHTG and ESCP for Lynch syndrome (updated third edition of Mallorca guidelines). NM_000535.7:c.33T>C was not identified in this paper.Does not name this variant
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PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.Sherloc refinement of ACMG-AMP variant classification criteria. NM_000535.7:c.33T>C 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
2 Likely benign · 1 Likely Benign · 1 Benign
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/525878/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/7-6045653-A-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr7-6006022-A-G?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/7-6006022-A-G
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000535.7%3Ac.33T%…
- OncoKB ↗www.oncokb.org/gene/PMS2/P11=
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=PMS2+c.33T%3EC
- 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 Likely benign (2 clinical laboratories) and as Likely Benign (1 clinical laboratory) and as Benign (1 clinical laboratory). (ClinVarID = 525878)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
Functional
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
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.