About PMS2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PMS2 c.705+24C>T, p.?
Classification
Likely benign
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely benign. Select a step to read what it means.
Likely benign.A likely benign 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: 1
Benign evidence criteria: 2
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
NM_000535.7:c.705+24C>T has an overall allele frequency of 1.18e-05 (19/1,610,524 alleles) in gnomAD v4.1, which is below the VCEP PM2 threshold of <0.00002 (<1 in 50,000 alleles). The variant is absent from gnomAD-Canada v1.0. Per the InSiGHT PMS2 VCEP v2.0.0, this meets PM2_Supporting.
Benign criteria applied · 2
BP4Supporting
BP4 · supporting
NM_000535.7:c.705+24C>T is an intronic variant. SpliceAI predicts no splicing impact with a maximum delta score of 0.04, which is ≤0.1. Per the InSiGHT PMS2 VCEP v2.0.0, intronic variants with SpliceAI delta ≤0.1 meet BP4_Supporting (Walker et al. 2023).
BP7Supporting
BP7 · supporting
NM_000535.7:c.705+24C>T is an intronic variant located at position +24 in intron 6 of PMS2, which is beyond the +7 canonical splice donor boundary. Per the InSiGHT PMS2 VCEP v2.0.0, intronic variants at or beyond -21/+7 meet BP7_Supporting. This criterion may be combined with BP4 as noted in the VCEP rule.
Recorded classification: Likely benign
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 Rule19 (Benign.Supporting >=2) with applied criteria: PM2 supporting, BP4 supporting benign, BP7 supporting benign; maps to Likely Benign.
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
19 / 1,610,524 alleles
gnomAD v4.1: 19 / 1,610,524 alleles. Recorded AF 1.17974e-05. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 7.95336e-06; MAF= 0.00080%, 2/251466 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 3.26627e-05; MAF= 0.00327%, 1/30616 alleles, homozygotes = 0).
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
SpliceAI score
0.040 maximum delta
Recorded SpliceAI maximum delta score: 0.040. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
No screenshot for this evidence
Functional evidence
Not recorded
No standalone functional evidence summary is recorded in evidence_summary.functional.
No listed criterion applied
OncoKB ↗
Somatic evidence
2 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV113734575, n = 2 times).
Context only
COSMIC ↗
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: 3 met · 13 not met · 0 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.705+24C>T is an intronic variant in PMS2 located at position +24 of intron 6, outside the canonical splice consensus region.
This variant is present in gnomAD v4.1 at an extremely low overall allele frequency of 1.18e-05 (19/1,610,524 alleles, no homozygotes), meeting PM2_Supporting per InSiGHT PMS2 VCEP criteria (allele frequency <0.00002).
SpliceAI predicts no splicing impact with a maximum delta score of 0.04, meeting BP4_Supporting per the InSiGHT PMS2 VCEP (delta ≤0.1 for intronic variants).
The variant is at intronic position +24, which is beyond the +7 canonical splice donor boundary, meeting BP7_Supporting per the InSiGHT PMS2 VCEP (intronic variants at or beyond -21/+7).
The variant is absent from ClinVar and no publications were identified that mention NM_000535.7:c.705+24C>T.
The variant has been observed in COSMIC (COSV113734575, n=2 somatic occurrences), but this does not constitute germline evidence of pathogenicity.
Criteria met: PM2_Supporting (extremely rare in population databases). Benign criteria met: BP4_Supporting (SpliceAI predicts no splice impact), BP7_Supporting (intronic variant beyond canonical splice region).
Per InSiGHT PMS2 VCEP v2.0.0 combination Rule 31, the co-occurrence of pathogenic supporting evidence (PM2) and benign supporting evidence (BP4, BP7) results in Uncertain Significance — Conflicting Evidence. While the variant also satisfies Rule 19 (≥2 benign supporting criteria for Likely Benign), the presence of pathogenic supporting evidence triggers the conflicting evidence rule.
No criteria match.
Met · 3
PM2 SupportingNM_000535.7:c.705+24C>T has an overall allele frequency of 1.18e-05 (19/1,610,524 alleles) in gnomAD v4.1, which is below the VCEP PM2 threshold of <0.00002 (<1 in 50,000 alleles). The variant is absent from gnomAD-Canada v1.0. Per the InSiGHT PMS2 VCEP v2.0.0, this meets PM2_Supporting. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 total AF = 1.18e-05 (19/1
- 610
- 524 alleles)
- below VCEP PM2 threshold of <0.00002
- grpmax FAF = 3.59e-05.
Sources
BP4 SupportingNM_000535.7:c.705+24C>T is an intronic variant. SpliceAI predicts no splicing impact with a maximum delta score of 0.04, which is ≤0.1. Per the InSiGHT PMS2 VCEP v2.0.0, intronic variants with SpliceAI delta ≤0.1 meet BP4_Supporting (Walker et al. 2023). Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.04
- below BP4 threshold of ≤0.1 for intronic variants.
Sources
BP7 SupportingNM_000535.7:c.705+24C>T is an intronic variant located at position +24 in intron 6 of PMS2, which is beyond the +7 canonical splice donor boundary. Per the InSiGHT PMS2 VCEP v2.0.0, intronic variants at or beyond -21/+7 meet BP7_Supporting. This criterion may be combined with BP4 as noted in the VCEP rule. Details ▾Hide ▴
Evidence considered
- Intronic variant at position +24
- beyond the +7 canonical splice donor boundary.
Sources
Not met · 13 · evaluated, threshold not reached
PS1 PS1 requires either a predicted missense substitution encoding the same amino acid change as a previously established pathogenic variant, or a variant affecting the same non-canonical splice nucleotide as a confirmed pathogenic splice variant with similar or worse SpliceAI prediction. NM_000535.7:c.705+24C>T is an intronic variant with SpliceAI max delta score of 0.04 (no predicted splice impact). No pathogenic variant has been established at the c.705+24 nucleotide position in PMS2. Details ▾Hide ▴
Evidence considered
- SpliceAI delta = 0.04
- no pathogenic comparator at c.705+24
- no ClinVar entries for this variant.
Sources
PS2 No de novo observations are available for NM_000535.7:c.705+24C>T. The variant is absent from ClinVar and no publications report de novo occurrence. PS2 requires confirmed de novo status (maternity and paternity confirmed) in a proband with MMR-deficient LS spectrum tumor. Details ▾Hide ▴
Evidence considered
- No de novo data available
- variant absent from ClinVar and literature.
Still missing
- No family studies or de novo testing data available.
Sources
PS3 No functional assay data are available for NM_000535.7:c.705+24C>T. The VCEP functional assay documentation and pilot variants spreadsheet do not include this variant. No calibrated functional odds, MMR function assay results, or monoallelic expression data exist for this variant. Details ▾Hide ▴
Evidence considered
- Variant absent from VCEP functional assay documentation and pilot variant spreadsheet.
Still missing
- No functional studies have been performed on this variant.
Sources
PP1 No co-segregation data are available for NM_000535.7:c.705+24C>T. The variant is absent from ClinVar and no publications report segregation analysis. PP1 requires co-segregation with disease in pedigrees with a combined Bayes Likelihood Ratio exceeding specified thresholds. Details ▾Hide ▴
Evidence considered
- No co-segregation data available
- variant absent from ClinVar and literature.
Still missing
- No family segregation studies available.
Sources
PP3 PP3 in the InSiGHT PMS2 VCEP requires either an HCI prior score >0.68 for missense variants or a SpliceAI delta score ≥0.2 for non-canonical splice variants. NM_000535.7:c.705+24C>T is an intronic variant (not missense) with HCI prior not available. SpliceAI max delta score is 0.04, which falls below the 0.2 threshold for predicted splice defects. PP3 is not met. Details ▾Hide ▴
Evidence considered
- Not a missense variant
- HCI prior not available
- SpliceAI delta = 0.04 (<0.2 threshold for PP3_Supporting).
Sources
PP4 No tumor phenotype data are available for NM_000535.7:c.705+24C>T. The variant is absent from ClinVar and no publications report MSI status, MMR protein expression, or tumor characteristics. PP4 requires evidence of MSI-H tumors and/or loss of MMR protein expression consistent with the variant location. Details ▾Hide ▴
Evidence considered
- No tumor phenotype data available
- variant absent from ClinVar and literature.
Still missing
- No tumor MSI/IHC data available.
Sources
BA1 The gnomAD v4.1 grpmax filtering allele frequency for NM_000535.7:c.705+24C>T is 3.59e-05 (0.00359%), which is far below the VCEP BA1 threshold of ≥0.0028 (0.28%). BA1 is not met. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 grpmax FAF = 3.59e-05
- well below BA1 threshold of 0.0028.
Sources
BS1 The gnomAD v4.1 grpmax filtering allele frequency for NM_000535.7:c.705+24C>T is 3.59e-05 (0.00359%), which is below the VCEP BS1 threshold range of ≥0.00028 and <0.0028 (0.028%-0.28%). BS1 is not met. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 grpmax FAF = 3.59e-05
- below BS1 lower bound 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 features. No such data are available. The variant is absent from ClinVar and no publications report trans co-occurrence data. Details ▾Hide ▴
Evidence considered
- No trans co-occurrence data available
- variant absent from ClinVar and literature.
Still missing
- No co-occurrence or phase data available.
Sources
BS3 BS3 requires calibrated functional assays showing benign functional odds (≤0.05 for Strong, >0.05 & ≤0.48 for Supporting), or for intronic variants, laboratory assays demonstrating no associated mRNA aberration with NMD inhibition. No functional studies have been performed on NM_000535.7:c.705+24C>T. The SpliceAI delta of 0.04 predicts no splicing impact but is an in silico tool, not a laboratory assay, and is addressed under BP4. Details ▾Hide ▴
Evidence considered
- No functional assay data available
- variant not listed in VCEP functional assay documentation.
Still missing
- No laboratory-based mRNA splicing or MMR functional assays performed.
Sources
cspec ↗vcep_functional_assay_svi_documentation_mmr
BS4 No co-segregation data are available for NM_000535.7:c.705+24C>T. BS4 requires lack of co-segregation with disease in pedigrees with a combined Bayes Likelihood Ratio below specified thresholds. No family studies have been reported. Details ▾Hide ▴
Evidence considered
- No co-segregation data available.
Still missing
- No family segregation studies available.
Sources
BP5 No tumor phenotype data are available for NM_000535.7:c.705+24C>T. BP5 requires evidence of MSS tumors and/or no loss of MMR protein expression, or BRAF V600E/MLH1 methylation in appropriate tumor contexts. No such data have been reported. Details ▾Hide ▴
Evidence considered
- No tumor phenotype data available.
Still missing
- No tumor MSS/IHC data available.
Sources
PS5 PS5 is not a defined criterion in the InSiGHT PMS2 VCEP v2.0.0 framework. Under generic ACMG/AMP, PS5 requires a different pathogenic variant at the same nucleotide position established by a reputable source. No such variant has been identified at c.705+24 in PMS2. The variant is absent from ClinVar. Details ▾Hide ▴
Not applicable · 13· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_000535.7:c.705+24C>T is an intronic variant at position +24 in intron 6 of PMS2. This variant does not fall into any PVS1 null-variant category (nonsense, frameshift, or canonical ±1,2 splice consensus). The VCEP PVS1 criteria for PMS2 are limited to nonsense/frameshift variants introducing PTC, large genomic alterations, IVS±1/±2 splice variants, and initiation codon variants. Details ▾Hide ▴
Evidence considered
- Intronic variant at c.705+24 — outside PVS1 null-variant scope.
Sources
PS4 VCEPPS4 is designated as Not Applicable by the InSiGHT PMS2 VCEP v2.0.0. Details ▾Hide ▴
PM1 VCEPPM1 is designated as Not Applicable by the InSiGHT PMS2 VCEP v2.0.0. Details ▾Hide ▴
PM3 N/APM3 requires observation of the variant in trans with a pathogenic variant. Per user directive, this criterion is trivially not applicable for this case context. Details ▾Hide ▴
Evidence considered
- Skipped per directive: trivially not_applicable.
PM4 VCEPPM4 requires a protein-length changing variant (in-frame deletion/insertion, stop-loss, or initiation codon change). NM_000535.7:c.705+24C>T is an intronic substitution with no protein consequence. Details ▾Hide ▴
Evidence considered
- Skipped per directive: trivially not_applicable for an intronic substitution.
PM5 N/APM5 requires a missense change at an amino acid residue where a different missense change has been classified. NM_000535.7:c.705+24C>T is an intronic variant and does not encode an amino acid change. PM5 is not applicable to intronic variants. Details ▾Hide ▴
Evidence considered
- Intronic variant with no protein consequence
- pm5_candidates confirms not eligible.
Sources
pm5_candidatescspec ↗
PM6 VCEPPM6 is designated as Not Applicable by the InSiGHT PMS2 VCEP v2.0.0. Details ▾Hide ▴
PP2 VCEPPP2 is designated as Not Applicable by the InSiGHT PMS2 VCEP v2.0.0 (missense variant in a gene with low rate of benign missense changes does not apply). Details ▾Hide ▴
PP5 VCEPPP5 is designated as Not Applicable by the InSiGHT PMS2 VCEP v2.0.0. Details ▾Hide ▴
BP1 VCEPBP1 is designated as Not Applicable by the InSiGHT PMS2 VCEP v2.0.0 (missense variant in a gene where only loss of function causes disease is not applicable). Details ▾Hide ▴
BP2 VCEPBP2 is designated as Not Applicable by the InSiGHT PMS2 VCEP v2.0.0. Details ▾Hide ▴
BP3 VCEPBP3 is not applicable — this is an intronic substitution, not an in-frame deletion/insertion in a repetitive region. Details ▾Hide ▴
Evidence considered
- Intronic substitution
- not an in-frame indel in a repetitive region.
Sources
BP6 VCEPBP6 is designated as Not Applicable by the InSiGHT PMS2 VCEP v2.0.0. Details ▾Hide ▴
Identifiers
- Gene
- PMS2
- Transcript
- NM_000535.7
- Coding (HGVS c.)
- NM_000535.7:c.705+24C>T
- Protein (HGVS p.)
- NP_000526.2:p.?
- GRCh38
- chr7:5999084 G>A
- GRCh37
- chr7:6038715 G>A
- COSMIC
- COSV113734575
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
—
Transcript span
—
Strand
—
Variants mapped
—
Source
UCSC ncbiRefSeqCurated
All variants in PMS2
—
Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
19 / 1,610,524 alleles
AF 1.18e-05 · 0 homozygotes · FAF 3.59e-05
gnomAD v2.1
2 / 251,466 alleles
AF 7.95e-06 · 0 homozygotes
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 1.2e-05 · 19 / 1,610,524 alleles · 0 hom · FAF 3.6e-05
| Middle Eastern1 / 5,966 | 0.00017 |
| South Asian7 / 91,000 | 7.7e-05 |
| Admixed American2 / 59,982 | 3.3e-05 |
| Remaining individuals1 / 62,368 | 1.6e-05 |
| African/African American1 / 74,914 | 1.3e-05 |
| European (non-Finnish)7 / 1,176,960 | 5.9e-06 |
0 alternate alleles recorded in 4 other groups: European (Finnish), Amish, East Asian, Ashkenazi Jewish.
gnomAD v2.1
AF 8e-06 · 2 / 251,466 alleles · 0 hom
| South Asian1 / 30,616 | 3.3e-05 |
| Admixed American1 / 34,590 | 2.9e-05 |
0 alternate alleles recorded in 6 other groups: African/African American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 1.17974e-05; MAF= 0.00118%, 19/1610524 alleles, homozygotes = 0) and has highest observed frequency in the Middle Eastern population (AF= 0.000167616; MAF= 0.01676%, 1/5966 alleles, homozygotes = 0); grpmax FAF= 3.59e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 7.95336e-06; MAF= 0.00080%, 2/251466 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 3.26627e-05; MAF= 0.00327%, 1/30616 alleles, homozygotes = 0).
gnomAD-Canada
Not available in 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.705+24C>T is an intronic variant. SpliceAI predicts no splicing impact with a maximum delta score of 0.04, which is ≤0.1. Per the InSiGHT PMS2 VCEP v2.0.0, intronic variants with SpliceAI delta ≤0.1 meet BP4_Supporting (Walker et al. 2023). Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.04
- below BP4 threshold of ≤0.1 for intronic variants.
Sources
BP7 SupportingNM_000535.7:c.705+24C>T is an intronic variant located at position +24 in intron 6 of PMS2, which is beyond the +7 canonical splice donor boundary. Per the InSiGHT PMS2 VCEP v2.0.0, intronic variants at or beyond -21/+7 meet BP7_Supporting. This criterion may be combined with BP4 as noted in the VCEP rule. Details ▾Hide ▴
Evidence considered
- Intronic variant at position +24
- beyond the +7 canonical splice donor boundary.
Sources
PP3 PP3 in the InSiGHT PMS2 VCEP requires either an HCI prior score >0.68 for missense variants or a SpliceAI delta score ≥0.2 for non-canonical splice variants. NM_000535.7:c.705+24C>T is an intronic variant (not missense) with HCI prior not available. SpliceAI max delta score is 0.04, which falls below the 0.2 threshold for predicted splice defects. PP3 is not met. Details ▾Hide ▴
Evidence considered
- Not a missense variant
- HCI prior not available
- SpliceAI delta = 0.04 (<0.2 threshold for PP3_Supporting).
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04).
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
19 / 1,610,524 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.040
Open source ↗
ClinVar
Captured ClinVar source record
Open source ↗
COSMIC
Captured COSMIC 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.705%2B24C%3ET
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/7-6038715-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr7-5999084-G-A?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/7-5999084-G-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000535.7%3Ac.705%…
- OncoKB ↗www.oncokb.org/gene/PMS2/?
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=125058900
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= 1.17974e-05; MAF= 0.00118%, 19/1610524 alleles, homozygotes = 0) and has highest observed frequency in the Middle Eastern population (AF= 0.000167616; MAF= 0.01676%, 1/5966 alleles, homozygotes = 0); grpmax FAF= 3.59e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 7.95336e-06; MAF= 0.00080%, 2/251466 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 3.26627e-05; MAF= 0.00327%, 1/30616 alleles, homozygotes = 0).
gnomAD-Canada
Not available in 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 = 0.04).
Somatic
This variant has previously been reported in somatic cancers (COSMIC; COSV113734575, n = 2 times).