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PMS2c.14A>TNot classified
Print report
Variant interpretation report

PMS2 c.14A>T, p.(Glu5Val)

NM_000535.7:c.14A>T NP_000526.2:p.(Glu5Val) View identifiers
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.

About PMS2

No gene-level summary was recorded for this case.

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

PM2_Supporting is met: NM_000535.7:c.14A>T is extremely rare in gnomAD v4.1 (AF=4.96e-06, 8/1,612,464 alleles, grpmax FAF=2.92e-06), which falls below the VCEP threshold of <0.00002 (<1 in 50,000 alleles). The variant is absent from gnomAD v2.1 and gnomAD-Canada v1.0.

Benign criteria applied · 1
BP4Supporting
BP4 · supporting

BP4_Supporting is met: the HCI prior probability for pathogenicity is 0.004, which falls below the VCEP threshold of <0.11 for BP4_Supporting. Multiple in silico predictors support a benign effect: REVEL score 0.498 (below typical pathogenic threshold), BayesDel score 0.008 (strongly benign), and SpliceAI delta 0.00 (no splicing impact).

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.

SpliceAI score
0.000 maximum delta

Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4 → SpliceAI ↗
ClinVar submissions
7 reported laboratory submissions

6 Uncertain significance · 1 Uncertain Significance.

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
COSMIC ↗Cancer Hotspots ↗
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 · 12 not met · 2 not assessed · 10 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP4BP5BP6BP7
Met Not met Not assessed Not applicable

NM_000535.7:c.14A>T (p.Glu5Val) is a missense variant in exon 1 of PMS2. It is extremely rare in population databases (gnomAD v4.1: 8/1,612,464 alleles, AF=4.96e-06), meeting PM2_Supporting per InSiGHT/ClinGen PMS2 VCEP v2.0.0.

Multiple in silico predictors support a benign effect: the HCI prior probability for pathogenicity is 0.004 (meeting BP4_Supporting), REVEL score is 0.498, BayesDel score is 0.008, and SpliceAI predicts no splicing impact (max delta = 0.00).

No functional data, segregation data, de novo observations, or tumor phenotype data (MSI/IHC) are available for this variant. ClinVar reports this variant as Uncertain Significance (VCV231310, 7 submitters, criteria provided single submitter).

The variant does not meet criteria for PVS1 (missense, not a null variant), PS1 (no same-amino-acid pathogenic comparator), PS3 (no functional data), PM5 (no same-residue pathogenic comparator), or any other pathogenic criterion.

The only criteria met are PM2_Supporting (extremely rare in gnomAD) and BP4_Supporting (benign in silico predictions including HCI prior <0.11). With one pathogenic supporting and one benign supporting criterion, the evidence is insufficient to reach a Likely Pathogenic or Likely Benign classification under the VCEP combining rules. The variant remains a Variant of Uncertain Significance.

Met · 2

PM2 SupportingPM2_Supporting is met: NM_000535.7:c.14A>T is extremely rare in gnomAD v4.1 (AF=4.96e-06, 8/1,612,464 alleles, grpmax FAF=2.92e-06), which falls below the VCEP threshold of <0.00002 (<1 in 50,000 alleles). The variant is absent from gnomAD v2.1 and gnomAD-Canada v1.0. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1: 8/1
  • 612
  • 464 alleles (AF=4.96e-06
  • grpmax FAF=2.92e-06)
  • gnomAD v2.1: absent
  • gnomAD-Canada: absent.
Sources
gnomad_v4 ↗
BP4 SupportingBP4_Supporting is met: the HCI prior probability for pathogenicity is 0.004, which falls below the VCEP threshold of <0.11 for BP4_Supporting. Multiple in silico predictors support a benign effect: REVEL score 0.498 (below typical pathogenic threshold), BayesDel score 0.008 (strongly benign), and SpliceAI delta 0.00 (no splicing impact). Details ▾Hide ▴
Evidence considered
  • HCI prior = 0.004 (<0.11). REVEL = 0.498. BayesDel = 0.008. SpliceAI max delta = 0.00.
Sources
hci_priorrevelbayesdelspliceai ↗

Not met · 12 · evaluated, threshold not reached

PS1 PS1 is not met: no different nucleotide change at Glu5 encoding the same Val substitution has been previously classified as Pathogenic by the InSiGHT/ClinGen VCEP for PMS2. Details ▾Hide ▴
Evidence considered
  • No VCEP-classified pathogenic comparator at Glu5 with same amino acid change identified in VCEP pilot variants spreadsheet or ClinVar.
Still missing
  • No established pathogenic missense at PMS2 codon 5 with a different nucleotide change.
PS3 PS3 is not met: no variant-specific functional assay data are available for NM_000535.7:c.14A>T (p.Glu5Val). OncoKB reports Unknown Oncogenic Effect with no variant-specific PMIDs. No calibrated functional odds data exist for this variant in the MMR functional assay SVI documentation. Details ▾Hide ▴
Evidence considered
  • OncoKB: Unknown Oncogenic Effect
  • no variant-specific functional evidence. MMR functional assay SVI documentation contains no entry for c.14A>T or p.E5V.
Still missing
  • No functional assay data (MMR activity
  • protein expression
  • or splicing) available for this variant.
PM5 PM5 is not met: no different missense variant at PMS2 residue Glu5 has been classified as Pathogenic or Likely Pathogenic by the VCEP. The PM5 candidate search identified zero same-residue comparators meeting the VCEP threshold. Details ▾Hide ▴
Evidence considered
  • Zero same-residue (Glu5) candidate comparators identified in ClinVar or VCEP pilot variants database. The closest variants at residue 5 (c.13G>A p.E5K
  • c.13G>C p.E5Q
  • c.14A>C p.E5A
  • c.14A>G p.E5G
  • c.15G>C/T p.E5D) are present in HCI priors but none have VCEP Pathogenic/Likely Pathogenic classification.
Still missing
  • No VCEP-classified pathogenic or likely pathogenic missense at Glu5.
PP1 PP1 is not met: no co-segregation data (Bayes Likelihood Ratio) are available for NM_000535.7:c.14A>T in any pedigree. The single full-text publication reviewed (PMID:25070057) is a general Lynch syndrome management guideline and contains no variant-specific segregation analysis. Details ▾Hide ▴
Evidence considered
  • No co-segregation data identified. PMID:25070057 reviewed and contains no variant-specific data.
Still missing
  • No pedigree or co-segregation analysis available.
Sources
25070057
PP3 PP3 is not met: the HCI prior probability for pathogenicity is 0.004, which is far below both the VCEP Moderate threshold (>0.81) and the Supporting threshold (>0.68 and ≤0.81). SpliceAI predicts no splicing impact (max delta score = 0.00, below the 0.2 threshold). REVEL score is 0.498 and BayesDel is 0.008, consistent with a benign in silico profile. Details ▾Hide ▴
Evidence considered
  • HCI prior = 0.004 (thresholds: >0.81=Moderate
  • >0.68=Supporting). SpliceAI max delta = 0.00. REVEL = 0.498. BayesDel = 0.008.
Sources
hci_priorspliceai ↗revelbayesdel
BA1 BA1 is not met: the gnomAD v4.1 grpmax filtering allele frequency is 2.92e-06, far below the VCEP stand-alone benign threshold of ≥0.0028 (0.28%). Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 grpmax FAF = 2.92e-06
  • threshold = 0.0028.
Sources
gnomad_v4 ↗
BS1 BS1 is not met: the gnomAD v4.1 grpmax filtering allele frequency is 2.92e-06, far below the VCEP strong benign threshold of ≥0.00028 (0.028%). Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 grpmax FAF = 2.92e-06
  • threshold = 0.00028.
Sources
gnomad_v4 ↗
BS2 BS2 is not met: no evidence of this variant occurring in trans with a known pathogenic PMS2 variant in a CRC patient over age 45 without CMMRD features. Details ▾Hide ▴
Evidence considered
  • No in trans co-occurrence data with a known pathogenic PMS2 variant identified.
Still missing
  • No phase-confirmed co-occurrence data.
BS3 BS3 is not met: no calibrated functional assay data are available for NM_000535.7:c.14A>T. No evidence of proficient MMR function or normal splicing has been demonstrated for this specific variant in laboratory assays. Details ▾Hide ▴
Evidence considered
  • No functional assay evidence for this variant. OncoKB reports Unknown Oncogenic Effect. No entry in MMR functional assay SVI documentation.
Still missing
  • No functional data to demonstrate proficient or deficient MMR activity.
BS4 BS4 is not met: no co-segregation data (lack of segregation with disease) are available for this variant. The single full-text publication reviewed (PMID:25070057) is a general guideline and contains no variant-specific segregation analysis. Details ▾Hide ▴
Evidence considered
  • No co-segregation or lack-of-segregation data identified.
Still missing
  • No pedigree co-segregation analysis available.
Sources
25070057
BP5 BP5 is not met: no tumor data demonstrating MSS status, intact MMR protein expression, or BRAF V600E/MLH1 methylation in carriers of this variant are available. Details ▾Hide ▴
Evidence considered
  • No tumor phenotype data (MSS
  • IHC
  • BRAF
  • MLH1 methylation) available for carriers.
Still missing
  • No MSS tumor data or IHC results to support a benign interpretation.
BP7 BP7 is not met: this criterion applies only to synonymous (silent) or intronic variants at or beyond positions -21/+7. NM_000535.7:c.14A>T is a missense variant (p.Glu5Val) and does not qualify. Details ▾Hide ▴
Evidence considered
  • Variant is missense (p.Glu5Val)
  • not synonymous or intronic.

Not assessed · 2 · no assessment recorded

PS2 PS2 is not assessed: no de novo observation data for this variant were identified in ClinVar submissions, literature, or any supporting databases. Details ▾Hide ▴
Evidence considered
  • No de novo reports found for NM_000535.7:c.14A>T in any source.
Still missing
  • No de novo testing or trio data available.
PP4 PP4 is not assessed: no tumor MSI/IHC data (MSI-H status, MMR protein expression) are available for patients carrying NM_000535.7:c.14A>T. The VCEP requires tumor phenotype data (CRC/endometrial MSI-H and/or loss of MMR protein expression consistent with PMS2) to apply this criterion. Details ▾Hide ▴
Evidence considered
  • No tumor phenotype data (MSI or IHC) available for any carrier of this variant.
Still missing
  • No MSI testing or MMR IHC results for carriers.
Not applicable · 10· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 is not applicable: NM_000535.7:c.14A>T is a missense variant (p.Glu5Val), not a nonsense, frameshift, canonical splice (±1,2), initiation codon, or large genomic alteration. The VCEP PVS1 rules for PMS2 apply only to null variant classes. Details ▾Hide ▴

No further detail was recorded.

PS4 VCEPPS4 is not applicable per InSiGHT/ClinGen PMS2 VCEP v2.0.0 specification. Details ▾Hide ▴

No further detail was recorded.

PM1 VCEPPM1 is not applicable per InSiGHT/ClinGen PMS2 VCEP v2.0.0 specification. Details ▾Hide ▴

No further detail was recorded.

PM6 VCEPPM6 is not applicable per InSiGHT/ClinGen PMS2 VCEP v2.0.0 specification. Details ▾Hide ▴

No further detail was recorded.

PP2 VCEPPP2 is not applicable per InSiGHT/ClinGen PMS2 VCEP v2.0.0 specification. Details ▾Hide ▴

No further detail was recorded.

PP5 VCEPPP5 is not applicable per InSiGHT/ClinGen PMS2 VCEP v2.0.0 specification. Details ▾Hide ▴

No further detail was recorded.

BP1 VCEPBP1 is not applicable per InSiGHT/ClinGen PMS2 VCEP v2.0.0 specification. Details ▾Hide ▴

No further detail was recorded.

BP2 VCEPBP2 is not applicable per InSiGHT/ClinGen PMS2 VCEP v2.0.0 specification. Details ▾Hide ▴

No further detail was recorded.

BP6 VCEPBP6 is not applicable per InSiGHT/ClinGen PMS2 VCEP v2.0.0 specification. Details ▾Hide ▴

No further detail was recorded.

PS5 N/APS5 is not applicable: not defined in the InSiGHT/ClinGen PMS2 VCEP v2.0.0 specification, and PP5 is explicitly listed as Not Applicable by this VCEP. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene
PMS2
Transcript
NM_000535.7
Coding (HGVS c.)
NM_000535.7:c.14A>T
Protein (HGVS p.)
NP_000526.2:p.(Glu5Val)
GRCh38
chr7:6009006 T>A
GRCh37
chr7:6048637 T>A
ClinVar
231310

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…
gnomAD v4.1 8 / 1,612,464 alleles AF 4.96e-06 · 0 homozygotes · FAF 2.92e-06
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 0 / 0 alleles AF 0 · 0 homozygotes · FAF 0

By genetic ancestry

gnomAD v4.1

AF 5e-06 · 8 / 1,612,464 alleles · 0 hom · FAF 2.9e-06
European (non-Finnish)8 / 1,179,840 6.8e-06
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.

gnomAD-Canada

AF 0 · 0 / 0 alleles · 0 hom

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 4.96135e-06; MAF= 0.00050%, 8/1612464 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 6.78058e-06; MAF= 0.00068%, 8/1179840 alleles, homozygotes = 0); grpmax FAF= 2.92e-06.

gnomAD v2.1

Absent from gnomAD v2.1.

Open the gnomAD-Canada detail page →

SpliceAI and Pangolin

Pangolin splice lossmagnitude shown
-0.000
Pangolin splice gain
0.010

Other predictors

REVEL
0.498
BayesDel
0.008

How the predictions were used

BP4 SupportingBP4_Supporting is met: the HCI prior probability for pathogenicity is 0.004, which falls below the VCEP threshold of <0.11 for BP4_Supporting. Multiple in silico predictors support a benign effect: REVEL score 0.498 (below typical pathogenic threshold), BayesDel score 0.008 (strongly benign), and SpliceAI delta 0.00 (no splicing impact). Details ▾Hide ▴
Evidence considered
  • HCI prior = 0.004 (<0.11). REVEL = 0.498. BayesDel = 0.008. SpliceAI max delta = 0.00.
Sources
hci_priorrevelbayesdelspliceai ↗
PP3 PP3 is not met: the HCI prior probability for pathogenicity is 0.004, which is far below both the VCEP Moderate threshold (>0.81) and the Supporting threshold (>0.68 and ≤0.81). SpliceAI predicts no splicing impact (max delta score = 0.00, below the 0.2 threshold). REVEL score is 0.498 and BayesDel is 0.008, consistent with a benign in silico profile. Details ▾Hide ▴
Evidence considered
  • HCI prior = 0.004 (thresholds: >0.81=Moderate
  • >0.68=Supporting). SpliceAI max delta = 0.00. REVEL = 0.498. BayesDel = 0.008.
Sources
hci_priorspliceai ↗revelbayesdel
BP7 BP7 is not met: this criterion applies only to synonymous (silent) or intronic variants at or beyond positions -21/+7. NM_000535.7:c.14A>T is a missense variant (p.Glu5Val) and does not qualify. Details ▾Hide ▴
Evidence considered
  • Variant is missense (p.Glu5Val)
  • not synonymous or intronic.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.498. BayesDel score = 0.00801122. HCI prior probability for pathogenicity = 0.004. Custom PP2 score = 0.062.

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

  • Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database.
    No paper-specific finding is recorded.
    PMID 24362816 ↗
  • Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the US Multi-society Task Force on colorectal cancer.
    Giardiello FM et al. · 2014
    US Multi-Society Task Force consensus guideline on genetic evaluation and management of Lynch syndrome. Discusses PMS2 at the gene level (lifetime CRC/endometrial cancer risks, IHC interpretation, surveillance recommendations) without reporting any individual PMS2 variants.
    Does not name this variant
    PMID 25070057 ↗
  • ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes.
    No paper-specific finding is recorded.
    PMID 25645574 ↗
  • 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.
    Richards S et al. · 2015
    No paper-specific finding is recorded.
    PMID 25741868 ↗
  • Management of patients with increased risk for familial pancreatic cancer: updated recommendations from the International Cancer of the Pancreas Screening (CAPS) Consortium.
    No paper-specific finding is recorded.
    PMID 31672839 ↗
  • Practice parameters for the identification and testing of patients at risk for dominantly inherited colorectal cancer--supporting documentation.
    Church J et al. · 2001
    No paper-specific finding is recorded.
    PMID 11598466 ↗
  • Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors.
    Trepanier A et al. · 2004
    No paper-specific finding is recorded.
    PMID 15604628 ↗
  • Lynch Syndrome.
    Adam MP et al. · 1993
    No paper-specific finding is recorded.
    PMID 20301390 ↗
  • Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
    No paper-specific finding is recorded.
    PMID 28492532 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 8 / 1,612,464 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.000 Open source ↗
ClinVar 6 Uncertain significance · 1 Uncertain Significance 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

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= 4.96135e-06; MAF= 0.00050%, 8/1612464 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 6.78058e-06; MAF= 0.00068%, 8/1179840 alleles, homozygotes = 0); grpmax FAF= 2.92e-06.

gnomAD v2.1

Absent from gnomAD v2.1.

ClinVar

This variant has been reported in ClinVar as Uncertain significance (6 clinical laboratories) and as Uncertain Significance (1 clinical laboratory). (ClinVarID = 231310)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.498. BayesDel score = 0.00801122. HCI prior probability for pathogenicity = 0.004. Custom PP2 score = 0.062.

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.