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PMS2c.1169C>GNot classified
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Variant interpretation report

PMS2 c.1169C>G, p.(Ala390Gly)

NM_000535.7:c.1169C>G NP_000526.2:p.(Ala390Gly) 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. 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

The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, satisfying PM2_Supporting (allele frequency <0.00002 in gnomAD v4).

Benign criteria applied · 1
BP4Supporting
BP4 · supporting

The PMS2-specific MAPP/PP2 prior probability for p.Ala390Gly is 0.0007, below the 0.11 threshold, satisfying BP4_Supporting for a missense variant with computational evidence against 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 v2.0 criteria-combination framework: matched Rule31 (Benign.Supporting >=1 + Pathogenic.Supporting >=1) with applied criteria: PM2 supporting, BP4 supporting benign; 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
0.118 maximum delta

Recorded SpliceAI maximum delta score: 0.118. Refer to the recorded PP3/BP4 rationale for interpretation.

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

1 Uncertain significance. ClinVar API review status: criteria provided, single submitter.

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, with the data and sources behind each one.

29 criteria with recorded statuses: 2 met · 14 not met · 0 not assessed · 13 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

NM_000535.7:c.1169C>G (p.Ala390Gly) is a missense substitution in PMS2 exon 11.

The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, meeting PM2_Supporting.

The PMS2-specific MAPP/PP2 prior probability for p.Ala390Gly is 0.0007, below the 0.11 threshold, meeting BP4_Supporting.

SpliceAI predicts no significant splice impact (max delta score 0.118), and no variant-specific functional, segregation, de novo, or tumor MSI/IHC data are available.

ClinVar lists this variant as Uncertain significance (single submitter, criteria provided).

With PM2_Supporting (pathogenic supporting) and BP4_Supporting (benign supporting) both applied, the evidence is conflicting and the variant is classified as Uncertain significance.

Met · 2

PM2 SupportingThe variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, satisfying PM2_Supporting (allele frequency <0.00002 in gnomAD v4). Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1
  • Absent from gnomAD v4.1
  • Absent from gnomAD-Canada v1.0
  • ClinVar submitter (Invitae) also applied PM2 (not present in population databases)
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗clinvar ↗
BP4 SupportingThe PMS2-specific MAPP/PP2 prior probability for p.Ala390Gly is 0.0007, below the 0.11 threshold, satisfying BP4_Supporting for a missense variant with computational evidence against impact. Details ▾Hide ▴
Evidence considered
  • HCI prior probability 0.0007 (< 0.11)
  • SpliceAI max delta score 0.118 (no significant splice impact)
Sources
hci_priorspliceai ↗

Not met · 14 · evaluated, threshold not reached

PS1 PS1 requires the same amino acid change (Ala390Gly) previously established as Pathogenic via a different nucleotide change; no such VCEP-established pathogenic comparator exists for this residue. Details ▾Hide ▴
Evidence considered
  • No prior Pathogenic/Likely Pathogenic p.Ala390Gly via alternate nucleotide change identified
Still missing
  • No established pathogenic same-amino-acid comparator in the PMS2 VCEP
PS2 PS2 requires a confirmed de novo occurrence (maternity and paternity confirmed) in a proband with an MMR-deficient LS-spectrum tumor; no de novo report exists for this variant. Details ▾Hide ▴
Evidence considered
  • No de novo report identified
Still missing
  • No de novo or parental-confirmation data available
PS3 No variant-specific functional data (calibrated functional odds, MMR functional assay, or monoallelic expression loss) are available for p.Ala390Gly. Details ▾Hide ▴
Evidence considered
  • OncoKB reports no reviewed variant-specific functional evidence
  • no calibrated functional assay data in the case
Still missing
  • No calibrated MMR functional assay result for this variant
Sources
oncokb ↗
PM5 PM5 requires a different missense change at Ala390 previously classified Pathogenic/Likely Pathogenic by the VCEP; no such same-residue comparator was identified, and PP3 is not met (a prerequisite for PM5 in this VCEP). Details ▾Hide ▴
Evidence considered
  • No same-residue (Ala390) pathogenic/likely pathogenic comparator identified
Still missing
  • Automated comparator search was skipped (variant mis-bucketed as non-missense)
  • manual ClinVar review of Ala390 missense comparators is recommended
Sources
pm5_candidates
PP1 No co-segregation data (Bayes likelihood ratio) with disease in affected family members are available for this variant. Details ▾Hide ▴
Evidence considered
  • No segregation data identified
Still missing
  • No pedigree/segregation data available
PP3 The PMS2-specific MAPP/PP2 prior probability is 0.0007 (far below the 0.68 supporting threshold), and SpliceAI predicts no significant splice impact (max delta 0.118, below 0.2); PP3 is not met. Details ▾Hide ▴
Evidence considered
  • HCI prior probability 0.0007 (< 0.68)
  • SpliceAI max delta score 0.118 (< 0.2)
Sources
hci_priorspliceai ↗
PP4 PP4 requires CRC/endometrial MSI-H tumor or loss of MMR protein expression consistent with the variant; no tumor MSI/IHC data are available. Details ▾Hide ▴
Evidence considered
  • No tumor MSI/IHC data identified
Still missing
  • No tumor MSI/IHC or protein-expression data available
BA1 BA1 requires a gnomAD v4 grpmax filtering allele frequency >=0.0028 (0.28%); the variant is absent from gnomAD, so BA1 is not met. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v4.1
Sources
gnomad_v4 ↗
BS1 BS1 requires a gnomAD v4 grpmax filtering allele frequency >=0.00028 (0.028%); the variant is absent from gnomAD, so BS1 is not met. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v4.1
Sources
gnomad_v4 ↗
BS2 BS2 requires co-occurrence in trans with a known pathogenic PMS2 variant in a patient with CRC after age 45 without CMMRD; no such co-occurrence data are available. Details ▾Hide ▴
Evidence considered
  • No in trans co-occurrence data identified
Still missing
  • No co-occurrence/phase data available
BS3 No variant-specific functional evidence demonstrating no damaging effect on PMS2 function (calibrated functional odds <=0.48, or proficient protein/mRNA assay) is available. Details ▾Hide ▴
Evidence considered
  • No benign functional assay data identified
Still missing
  • No calibrated functional assay result for this variant
BS4 BS4 requires lack of co-segregation with disease in affected family members; no segregation data are available for this variant. Details ▾Hide ▴
Evidence considered
  • No segregation data identified
Still missing
  • No pedigree/segregation data available
BP5 BP5 requires tumor data indicating an alternate molecular basis (MSS tumors, no loss of MMR expression, or BRAF/MLH1 methylation); no such tumor data are available. Details ▾Hide ▴
Evidence considered
  • No tumor/alternate-molecular-basis data identified
Still missing
  • No tumor MSI/IHC/methylation data available
BP7 BP7 applies only to synonymous (silent) or intronic variants at or beyond -21/+7; c.1169C>G is a missense substitution and does not qualify. Details ▾Hide ▴
Evidence considered
  • Missense substitution p.Ala390Gly (not synonymous/intronic)
Not applicable · 13· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/Ac.1169C>G is a missense substitution (p.Ala390Gly), not a null variant (nonsense, frameshift, canonical splice, initiation codon, or large deletion); it does not fall within any PVS1 null-variant bucket in the PMS2 VCEP. Details ▾Hide ▴
Evidence considered
  • Missense substitution p.Ala390Gly
  • PVS1 null-variant rules do not apply
Sources
pvs1_variant_assessment
PS4 VCEPThe PMS2 VCEP does not use PS4 for MMR variant classification because tumor IHC/MSI data are assessed under PP4 instead. Details ▾Hide ▴
Evidence considered
  • VCEP marks PS4 as Not applicable (proband counting not used)
Sources
cspec ↗
PM1 VCEPThe PMS2 VCEP states there are no recognized mutational hotspots usable for classification; pathogenic variant distribution is generalized across MMR functional domains. Details ▾Hide ▴
Evidence considered
  • VCEP marks PM1 as Not applicable
  • variant also not in a cancerhotspots.org significant hotspot
Sources
cspec ↗
PM3 N/ARecessive (in trans) co-occurrence evidence; no CMMRD biallelic co-occurrence data present for this missense variant. Details ▾Hide ▴

No further detail was recorded.

PM4 VCEPProtein-length-changing variant (in-frame indel/stop-loss); not applicable to a missense substitution. Details ▾Hide ▴

No further detail was recorded.

PM6 VCEPThe PMS2 VCEP marks PM6 as Not applicable (assumed de novo evidence is consolidated under the PS2 points system); no assumed de novo report exists for this variant. Details ▾Hide ▴
Evidence considered
  • VCEP marks PM6 as Not applicable
Sources
cspec ↗
PP2 VCEPThe PMS2 VCEP states PP2 does not apply (missense variant in a gene with a low rate of benign missense variation is not used). Details ▾Hide ▴
Evidence considered
  • VCEP marks PP2 as Not applicable
Sources
cspec ↗
PP5 VCEPThe PMS2 VCEP does not permit PP5 (per the ClinGen SVI VCEP Review Committee); the only ClinVar submission is a single-submitter Uncertain significance, not a 3-star expert-panel Pathogenic assertion. Details ▾Hide ▴
Evidence considered
  • VCEP marks PP5 as Not Applicable
  • ClinVar is single-submitter VUS (no expert panel)
Sources
cspec ↗clinvar ↗
BP1 VCEPThe PMS2 VCEP states BP1 does not apply (missense variant in a gene where primarily truncating variants cause disease is not used). Details ▾Hide ▴
Evidence considered
  • VCEP marks BP1 as Not applicable
Sources
cspec ↗
BP2 VCEPThe PMS2 VCEP does not use BP2 (BS2 is used instead for co-occurrence evidence). Details ▾Hide ▴
Evidence considered
  • VCEP marks BP2 as Not applicable (BS2 used instead)
Sources
cspec ↗
BP3 VCEPIn-frame deletion/insertion in a repetitive region; not applicable to a missense substitution. Details ▾Hide ▴

No further detail was recorded.

BP6 VCEPThe PMS2 VCEP does not permit BP6 (per the ClinGen SVI VCEP Review Committee); the only ClinVar submission is a single-submitter Uncertain significance, not a 3-star expert-panel Benign assertion. Details ▾Hide ▴
Evidence considered
  • VCEP marks BP6 as Not Applicable
  • ClinVar is single-submitter VUS (no expert panel)
Sources
cspec ↗clinvar ↗
PS5 N/APS5 is not defined in the InSiGHT Hereditary Colorectal Cancer/Polyposis PMS2 VCEP v2.0 (same-residue missense evidence is addressed by PM5). Details ▾Hide ▴
Evidence considered
  • No PS5 rule present in the PMS2 VCEP rule set
Sources
cspec ↗

Identifiers

Gene
PMS2
Transcript
NM_000535.7
Coding (HGVS c.)
NM_000535.7:c.1169C>G
Protein (HGVS p.)
NP_000526.2:p.(Ala390Gly)
GRCh38
chr7:5987596 G>C
GRCh37
chr7:6027227 G>C
ClinVar
3664593, 1355905

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 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

SpliceAI acceptor lossat +24 bp
0.056
SpliceAI acceptor gainat -474 bp
0.118
SpliceAI donor lossat -185 bp
0.039
SpliceAI donor gainat +25 bp
0.009
Pangolin splice lossmagnitude shown
-0.213
Pangolin splice gain
0.079

Other predictors

REVEL
0.242
BayesDel
-0.253

How the predictions were used

BP4 SupportingThe PMS2-specific MAPP/PP2 prior probability for p.Ala390Gly is 0.0007, below the 0.11 threshold, satisfying BP4_Supporting for a missense variant with computational evidence against impact. Details ▾Hide ▴
Evidence considered
  • HCI prior probability 0.0007 (< 0.11)
  • SpliceAI max delta score 0.118 (no significant splice impact)
Sources
hci_priorspliceai ↗
PP3 The PMS2-specific MAPP/PP2 prior probability is 0.0007 (far below the 0.68 supporting threshold), and SpliceAI predicts no significant splice impact (max delta 0.118, below 0.2); PP3 is not met. Details ▾Hide ▴
Evidence considered
  • HCI prior probability 0.0007 (< 0.68)
  • SpliceAI max delta score 0.118 (< 0.2)
Sources
hci_priorspliceai ↗
BP7 BP7 applies only to synonymous (silent) or intronic variants at or beyond -21/+7; c.1169C>G is a missense substitution and does not qualify. Details ▾Hide ▴
Evidence considered
  • Missense substitution p.Ala390Gly (not synonymous/intronic)

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.12). REVEL score = 0.242. BayesDel score = -0.253443. HCI prior probability for pathogenicity = 0.0007. MAPP score = 2.26. Custom PP2 score = 0.005.

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 Captured gnomAD v4.1 source record Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.118 Open source ↗
ClinVar 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

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 Uncertain significance (1 clinical laboratory). (ClinVarID = 1355905)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.12). REVEL score = 0.242. BayesDel score = -0.253443. HCI prior probability for pathogenicity = 0.0007. MAPP score = 2.26. Custom PP2 score = 0.005.

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.