Variant classification summary

NM_000535.7:c.86G>C

PMS2 · NP_000526.2:p.(Gly29Ala) · NM_000535.7

GRCh37: chr7:6045600 C>G · GRCh38: chr7:6005969 C>G

Gene: PMS2 Transcript: NM_000535.7

Final call

PP3 moderate BS1 strong

Variant details

Gene

PMS2

Transcript

NM_000535.7

Protein

NP_000526.2:p.(Gly29Ala)

gnomAD AF

0.0005016340356209832 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000535.7:c.86G>C (p.Gly29Ala) is a missense variant in exon 2 of PMS2, a gene in which loss-of-function is an established mechanism for Lynch syndrome.

2

This variant is present in gnomAD v4.1 at an allele frequency of 0.050% (808/1,610,736 alleles, grpmax FAF=0.037%), which meets the VCEP PMS2 BS1_Strong threshold (grpmax FAF ≥ 0.028% and < 0.28%). One homozygote is observed in both gnomAD v2 and v4, further supporting that this variant is unlikely to be highly penetrant.

3

The HCI MAPP/PP2 Prior P score of 0.8883 exceeds the VCEP PP3_Moderate threshold (>0.81), providing in silico evidence for a deleterious effect.

4

This variant is reported in ClinVar as Likely benign by 10 clinical laboratories and as Benign by 2 laboratories, though 5 laboratories classify it as Uncertain significance. The overall ClinVar classification is Likely benign with review status of criteria provided, single submitter.

5

SpliceAI predicts no splicing impact (max delta score 0.00), and the variant does not lie in a statistically significant mutational hotspot.

6

No functional studies, segregation data, tumor phenotype data, or de novo observations are available for this variant. No peer-reviewed publication specifically mentions NM_000535.7:c.86G>C.

Final determination: Rule22 in the 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 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	PVS1 is not applicable to this missense variant (c.86G>C, p.Gly29Ala). The ClinGen InSiGHT PMS2 VCEP v2.0.0 restricts PVS1 to null variants: nonsense/frameshift introducing PTC ≤ codon 798, canonical ±1,2 splice variants, initiation codon variants, and large genomic alterations.	cspec pvs1_variant_assessment
PS1	Not met	PS1 requires a different nucleotide change producing the same amino acid change (p.Gly29Ala) that has been classified as Pathogenic or Likely Pathogenic by this VCEP. No such comparator variant exists; c.86G>C is the only nucleotide change producing p.Gly29Ala in the PMS2 HCI priors database.	hci_prior
PS2	Not met	No de novo observations have been reported for NM_000535.7:c.86G>C in any available data source. PS2 requires documented de novo occurrence with confirmed maternity and paternity in a patient with an MMR-deficient LS-spectrum tumor.
PS3	Not met	No variant-specific functional assay data exist for NM_000535.7:c.86G>C (p.Gly29Ala). The ClinGen InSiGHT functional assay SVI documentation lists calibrated CIMRA, chemical selection, CRISPR, and cDNA-based assays, but none have tested this variant. OncoKB classifies this variant as Unknown Oncogenic Effect with no curated functional evidence.	oncokb vcep_functional_assay_svi_documentation_mmr
PS4	N/A	PS4 is marked Not Applicable by the ClinGen InSiGHT PMS2 VCEP v2.0.0.	cspec
PS5	N/A	PS5 is not defined in the ClinGen InSiGHT PMS2 VCEP v2.0.0 criteria set. The VCEP framework does not include PS5 among its specified criteria.	cspec
PM1	N/A	PM1 is marked Not Applicable by the ClinGen InSiGHT PMS2 VCEP v2.0.0.	cspec
PM2	Not met	Per VCEP PMS2 rule, PM2_Supporting requires absence or extremely rare allele frequency <0.00002 (<1 in 50,000 alleles) in gnomAD v4. This variant is present in gnomAD v4 at AF=0.0005016 (808/1,610,736 alleles, grpmax FAF=0.00037135), which is approximately 25-fold above the PM2 threshold. PM2 is not met.	gnomad_v4 cspec
PM5	Not met	PM5 requires a different missense change at amino acid residue Gly29 classified as Pathogenic or Likely Pathogenic by this VCEP. The VCEP pilot variants spreadsheet contains no PMS2 missense variants at codon 29. No same-residue comparator with a VCEP P/LP classification exists.	pm5_candidates vcep_vcep_pilot_variants_mmr cspec
PM6	N/A	PM6 is marked Not Applicable by the ClinGen InSiGHT PMS2 VCEP v2.0.0.	cspec
PP1	Not met	No co-segregation data are available for NM_000535.7:c.86G>C. PP1 requires co-segregation with disease in pedigrees with a combined Bayes Likelihood Ratio meeting VCEP thresholds.
PP2	N/A	PP2 is marked Not Applicable by the ClinGen InSiGHT PMS2 VCEP v2.0.0.	cspec
PP3	Met	The HCI MAPP/PP2 Prior P score for p.Gly29Ala (PMS2_00179) is 0.8883, which exceeds the VCEP PP3_Moderate threshold of >0.81. This in silico prior probability supports a pathogenic computational prediction.	hci_prior cspec
PP4	Not met	No tumor MSI/IHC data are available for NM_000535.7:c.86G>C carriers. PP4 requires MSI-H colorectal/endometrial tumors with MMR protein expression loss consistent with variant location.
PP5	N/A	PP5 is marked Not Applicable by the ClinGen InSiGHT PMS2 VCEP v2.0.0.	cspec
BA1	Not met	Per VCEP PMS2 rule, BA1 requires gnomAD v4 grpmax filtering allele frequency ≥ 0.0028 (0.28%). This variant has grpmax FAF = 0.00037135 (0.037%), which is approximately 7.5-fold below the BA1 threshold.	gnomad_v4 cspec
BS1	Met	Per VCEP PMS2 rule, BS1_Strong applies when gnomAD v4 grpmax filtering allele frequency is ≥ 0.00028 (0.028%) and < 0.0028 (0.28%), and the variant is excluded as a founder pathogenic variant. The grpmax FAF for this variant is 0.00037135 (0.037%), which falls within this range. The variant is observed across multiple populations with highest frequency in Ashkenazi Jewish (0.699%), but there is no definitive evidence of founder pathogenic status. One homozygote is observed in gnomAD v4, further supporting that this variant is unlikely to be highly penetrant.	gnomad_v4 gnomad_v2 cspec
BS2	Not met	No evidence of co-occurrence in trans with a known pathogenic PMS2 variant in a patient with colorectal cancer after age 45 without CMMRD features. BS2 requires confirmed phase with a pathogenic variant and specific clinical presentation.
BS3	Not met	No functional assay data demonstrating normal MMR function for NM_000535.7:c.86G>C exist. The VCEP functional assay documentation defines calibrated assays (CIMRA, chemical selection, cDNA analysis) but this variant has not been tested in any of them.	vcep_functional_assay_svi_documentation_mmr oncokb
BS4	Not met	No co-segregation data are available to demonstrate lack of segregation with disease. BS4 requires a combined Bayes Likelihood Ratio meeting VCEP thresholds from pedigrees.
BP1	N/A	BP1 is marked Not Applicable by the ClinGen InSiGHT PMS2 VCEP v2.0.0.	cspec
BP2	N/A	BP2 is marked Not Applicable by the ClinGen InSiGHT PMS2 VCEP v2.0.0.	cspec
BP3	N/A	BP3 applies to in-frame deletions/insertions in repetitive regions without a known function. This is a single-nucleotide missense substitution.
BP4	Not met	Per VCEP PMS2 rule, BP4_Supporting requires an HCI MAPP/PP2 Prior P score <0.11. The HCI prior for p.Gly29Ala is 0.8883, which is far above the benign threshold and instead supports pathogenicity (PP3_Moderate).	hci_prior cspec
BP5	Not met	No tumor data (MSS status, MMR protein expression) are available for carriers of this variant. BP5 requires CRC/endometrial tumors with MSS and/or no loss of MMR protein expression or LS spectrum tumors with inconsistent protein loss.
BP6	N/A	BP6 is marked Not Applicable by the ClinGen InSiGHT PMS2 VCEP v2.0.0.	cspec
BP7	N/A	BP7 applies to synonymous (silent) or intronic variants at or beyond -21/+7. NM_000535.7:c.86G>C is a missense variant producing p.Gly29Ala and does not qualify.	cspec

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