Classification rationale

PM2 BP4 Uncertain Significance - Conflicting Evidence

PMS2 c.1169C>G missense

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.¹ The PMS2-specific MAPP/PP2 prior probability for p.Ala390Gly is 0.0007, below the 0.11 threshold, meeting BP4_Supporting.² 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.³ ClinVar lists this variant as Uncertain significance (single submitter, criteria provided).⁴ With PM2_Supporting (pathogenic supporting) and BP4_Supporting (benign supporting) both applied, the evidence is conflicting and the variant is classified as Uncertain significance.

PM2 + BP4 → Uncertain Significance - Conflicting Evidence

1 gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

2 hci_prior

3 spliceai ↗

4 clinvar ↗

Gene diagram · NM_000535.7 · variants mapped to exon structure

PMS2 NM_000535.7

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 14 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 2

Strength Supporting Moderate Strong Very strong

✓

PM2 supporting Pathogenic

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

Absent from gnomAD v2.1Absent from gnomAD v4.1Absent from gnomAD-Canada v1.0

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗clinvar ↗

✓

BP4 supporting Benign

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.

HCI prior probability 0.0007 (< 0.11)SpliceAI max delta score 0.118 (no significant splice impact)

spliceai ↗

Assessed · not applied · 14 not met · 0 not assessed

Pathogenic

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.

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.

PS3 No variant-specific functional data (calibrated functional odds, MMR functional assay, or monoallelic expression loss) are available for p.Ala390Gly.

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).

PP1 No co-segregation data (Bayes likelihood ratio) with disease in affected family members are available for this variant.

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.

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.

Benign

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.

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.

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.

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.

BS4 BS4 requires lack of co-segregation with disease in affected family members; no segregation data are available for this variant.

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.

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.

N/A · 12 PVS1 · PS4 · PM1 · PM3 · PM4 · PM6 · PP2 · PP5 · BP1 · BP2 · BP3 · BP6

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

Absent from gnomAD v4.1.

v2.1

Absent from gnomAD v2.1.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory). (ClinVarID = 1355905)

ClinVar ↗

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.

SpliceAI ↗

Functional Unknown Oncogenic Effect

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.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

9Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots