Variant classification summary

NM_000535.7:c.1169C>G

PMS2 · NP_000526.2:p.(Ala390Gly) · NM_000535.7

GRCh37: chr7:6027227 G>C · GRCh38: chr7:5987596 G>C

Gene: PMS2 Transcript: NM_000535.7

Final call

PM2 supporting BP4 supporting benign

Variant details

Gene

PMS2

Transcript

NM_000535.7

Protein

NP_000526.2:p.(Ala390Gly)

gnomAD AF

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

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

2

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

3

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

4

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.

5

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

6

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

Final determination: Rule31 in the 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 is satisfied by the adjudicated criteria, so the variant is classified as Uncertain Significance - Conflicting Evidence.

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	N/A	c.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.	pvs1_variant_assessment
PS1	Not met	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	Not met	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	Not met	No variant-specific functional data (calibrated functional odds, MMR functional assay, or monoallelic expression loss) are available for p.Ala390Gly.	oncokb
PS4	N/A	The PMS2 VCEP does not use PS4 for MMR variant classification because tumor IHC/MSI data are assessed under PP4 instead.	cspec
PS5	N/A	PS5 is not defined in the InSiGHT Hereditary Colorectal Cancer/Polyposis PMS2 VCEP v2.0 (same-residue missense evidence is addressed by PM5).	cspec
PM1	N/A	The PMS2 VCEP states there are no recognized mutational hotspots usable for classification; pathogenic variant distribution is generalized across MMR functional domains.	cspec
PM2	Met	The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, satisfying PM2_Supporting (allele frequency <0.00002 in gnomAD v4).	gnomad_v2 gnomad_v4 gnomad_canada clinvar
PM5	Not met	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).	pm5_candidates
PM6	N/A	The 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.	cspec
PP1	Not met	No co-segregation data (Bayes likelihood ratio) with disease in affected family members are available for this variant.
PP2	N/A	The PMS2 VCEP states PP2 does not apply (missense variant in a gene with a low rate of benign missense variation is not used).	cspec
PP3	Not met	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.	hci_prior spliceai
PP4	Not met	PP4 requires CRC/endometrial MSI-H tumor or loss of MMR protein expression consistent with the variant; no tumor MSI/IHC data are available.
PP5	N/A	The 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.	cspec clinvar
BA1	Not met	BA1 requires a gnomAD v4 grpmax filtering allele frequency >=0.0028 (0.28%); the variant is absent from gnomAD, so BA1 is not met.	gnomad_v4
BS1	Not met	BS1 requires a gnomAD v4 grpmax filtering allele frequency >=0.00028 (0.028%); the variant is absent from gnomAD, so BS1 is not met.	gnomad_v4
BS2	Not met	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	Not met	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	Not met	BS4 requires lack of co-segregation with disease in affected family members; no segregation data are available for this variant.
BP1	N/A	The PMS2 VCEP states BP1 does not apply (missense variant in a gene where primarily truncating variants cause disease is not used).	cspec
BP2	N/A	The PMS2 VCEP does not use BP2 (BS2 is used instead for co-occurrence evidence).	cspec
BP4	Met	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 spliceai
BP5	Not met	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.
BP6	N/A	The 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.	cspec clinvar
BP7	Not met	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.
BP3	N/A	In-frame deletion/insertion in a repetitive region; not applicable to a missense substitution.
PM3	N/A	Recessive (in trans) co-occurrence evidence; no CMMRD biallelic co-occurrence data present for this missense variant.
PM4	N/A	Protein-length-changing variant (in-frame indel/stop-loss); not applicable to a missense substitution.

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