Variant classification summary

NM_000535.7:c.497T>C

PMS2 · NP_000526.2:p.(Leu166Pro) · NM_000535.7

GRCh37: chr7:6042124 A>G · GRCh38: chr7:6002493 A>G

Gene: PMS2 Transcript: NM_000535.7

Final call

VUS

PP3 moderate BS1 strong

Variant details

Gene

PMS2

Transcript

NM_000535.7

Protein

NP_000526.2:p.(Leu166Pro)

gnomAD AF

0.00013713029115056658 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

VUS: PP3 (moderate) because the PMS2 HCI MAPP/PP2 prior of 0.9595 exceeds the 0.81 threshold for a damaging missense prediction.

2

VUS: BS1 (strong) because gnomAD v4.1 Grpmax FAF 0.00242754 lies within the PMS2 VCEP 0.00028-0.0028 benign frequency band.

Final determination: Under Rule22 of the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel PMS2 Version 2.0 criteria-combination framework, one benign strong criterion (BS1) together with one pathogenic moderate criterion (PP3) is conflicting evidence, and the first matching rule therefore returns uncertain significance; the applied criteria and the rule match are exactly those of the deterministic derivation.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	Not met	Not met: PMS2 c.497T>C is a missense substitution, not a nonsense, frameshift, splice-site, initiation-codon or copy-number null, and SpliceAI max delta 0.012 excludes a splice consequence.	cspec vcep_pvs1_decisiontree_mmr spliceai
PS1	Not met	Not met: Leu166 is a CTN codon, so only c.497T>C itself can encode p.Leu166Pro - no alternate nucleotide change exists for PS1.	cspec clinvar vcep_vcep_pilot_variants_mmr
PS2	Not assessed	Not assessed: with no proband parental testing or tumor data, zero of the >=0.5 de novo points required for PS2_Supporting could be assigned.	cspec PMID:24113346
PS3	Not assessed	Not assessed: no calibrated MMR functional assay or functional-odds result exists for c.497T>C (p.Leu166Pro), so the VCEP PS3 threshold of functional odds >2.08 cannot be evaluated.	cspec vcep_functional_assay_svi_documentation_mmr vcep_functional_assay_flowchart vcep_vcep_pilot_variants_mmr clinvar oncokb
PS4	N/A	Not applicable: the InSiGHT PMS2 VCEP (CSPEC v2.0) sets PS4 applicability to Not Applicable, and no case-control enrichment data exist for p.Leu166Pro.	cspec PMID:24113346 PMID:25980754 PMID:27443514
PM1	N/A	Not applicable: the PMS2 VCEP specification lists PM1 as Not Applicable and its domain_tables entry is empty, so no approved domain list exists to test residue 166.	cspec vcep_mmr_functional_domains
PM2	Not met	Not met: gnomAD v4.1 total AF 0.00013713 is about 7-fold above the 0.00002 gnomAD-v4 rarity threshold.	cspec gnomad_v4 gnomad_v2 gnomad_canada
PM3	Not assessed	Not assessed: the PMS2 VCEP PM3 rule requires a co-occurring pathogenic/likely pathogenic PMS2 variant in trans and a CMMRD-consistent proband, and neither is documented.	cspec PMID:24113346
PM4	N/A	Not applicable: the InSiGHT PMS2 v2.0 VCEP marks PM4 not applicable and c.497T>C is a missense SNV with no protein-length change.	cspec
PM5	Not met	Not met: the only other missense at residue 166, p.Leu166Gln, is a single-submitter ClinVar VUS, so no VCEP-pathogenic comparator exists for PM5.	cspec pm5_candidates clinvar vcep_vcep_pilot_variants_mmr
PM6	N/A	Not applicable: the InSiGHT PMS2 v2.0 specification marks every PM6 strength tier as not applicable, folding assumed-de-novo probands into the PS2 point total instead.	cspec
PP1	Not assessed	Not assessed: no pedigree or relative genotypes exist for this variant, so the combined Bayes likelihood ratio needed for PP1 (>=2.08) cannot be computed.	cspec PMID:24113346
PP2	N/A	Not applicable: the PMS2 VCEP marks PP2 Not Applicable, replacing it with the gene-specific HCI missense prior (0.9595 for this variant) on the PP3/BP4 path.	cspec hci_prior vcep_hci_priors_pms2
PP3	Met	Met at Moderate: the PMS2 HCI MAPP/PP2 prior for c.497T>C (p.L166P) is 0.9595, above the VCEP PP3_Moderate threshold of >0.81.	cspec vcep_hci_priors_pms2 hci_prior
PP4	Not assessed	Not assessed: CSPEC PP4 requires tumour MSI-H and/or MMR-protein-loss data at a 1-3 tumour threshold, and no tumour phenotype data exist for this case.	cspec
PP5	Not met	Not met: ClinVar VCV000135944 has zero expert-panel submissions (1 star, conflicting single-lab classifications), so no expert-panel pathogenic assertion exists to trigger PP5.	cspec clinvar
BA1	Not met	Not met: gnomAD v4.1 grpmax filtering AF 0.00242754 falls below the 0.0028 stand-alone BA1 threshold.	cspec gnomad_v4 gnomad_v2 gnomad_canada clinvar
BS1	Met	Met at Strong: gnomAD v4.1 grpmax filtering AF 0.00242754 lies within the 0.00028-0.0028 benign-strong BS1 band.	cspec gnomad_v4 gnomad_v2 gnomad_canada clinvar
BS2	Not met	Not met: no source reports c.497T>C in trans with a pathogenic PMS2 variant, the observation the BS2 rule requires.	cspec clinvar PMID:24113346
BS3	Not assessed	Not assessed: no MMR functional assay shows variant-specific proficient function for c.497T>C (p.Leu166Pro), so the VCEP BS3 requirement for calibrated functional odds <=0.05 cannot be applied.	cspec vcep_functional_assay_svi_documentation_mmr vcep_functional_assay_flowchart vcep_vcep_pilot_variants_mmr clinvar oncokb
BS4	Not assessed	Not assessed: no segregation analysis exists, so the combined Bayes likelihood ratio required for BS4 (<0.05 or <=0.48) cannot be derived.	cspec PMID:24113346
BP1	N/A	Not applicable: the PMS2 VCEP marks BP1 Not Applicable, and PMS2 missense variants are an established mechanism, so truncating-only logic does not hold.	cspec vcep_vcep_pilot_variants_mmr
BP2	N/A	Not applicable: the PMS2 ClinGen InSiGHT VCEP v2.0 marks BP2 as not applicable and directs that BS2 is used instead.	cspec
BP3	N/A	Not applicable: the InSiGHT PMS2 v2.0 VCEP marks BP3 not applicable, and c.497T>C is a missense SNV, not an in-frame indel in a repetitive region.	cspec
BP4	Not met	Not met: the PMS2 missense BP4 rule requires an HCI MAPP/PP2 prior below 0.11, but c.497T>C (p.L166P) scores 0.9595.	cspec vcep_hci_priors_pms2 hci_prior
BP5	Not assessed	Not assessed: CSPEC BP5 requires 2-4 MSS/no-MMR-loss tumours (or BRAF V600E/MLH1 methylation), and no tumour data exist for this case.	cspec
BP6	Not met	Not met: ClinVar VCV000135944 carries no expert-panel benign classification (0 expert-panel submissions, 1 star), so aggregate single-lab benign labels cannot trigger BP6.	cspec clinvar
BP7	N/A	Not applicable: BP7 requires a synonymous or deep-intronic variant, but c.497T>C is a missense change (p.Leu166Pro).	cspec

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