Variant classification summary

NM_000535.7:c.736_741delinsTGTGTGTGAAG

PMS2 · NP_000526.2:p.(Pro246CysfsTer3) · NM_000535.7

GRCh37: chr7:6037019 AGGGGG>CTTCACACACA · GRCh38: chr7:5997388 AGGGGG>CTTCACACACA

Gene: PMS2 Transcript: NM_000535.7

Final call

Pathogenic

PVS1 very strong PM2 supporting PP5 supporting

Variant details

Gene

PMS2

Transcript

NM_000535.7

Protein

NP_000526.2:p.(Pro246CysfsTer3)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000535.7:c.736_741delinsTGTGTGTGAAG (p.Pro246CysfsTer3) is a frameshift indel in exon 7 of PMS2 that introduces a premature termination codon at amino acid position 248, meeting PVS1 at Very Strong strength under the InSiGHT PMS2 VCEP v2.0.0 (PTC ≤ codon 798).

2

The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0 population databases, meeting PM2_Supporting under InSiGHT PMS2 VCEP (allele frequency <0.00002).

3

This variant has been classified as Pathogenic by the InSiGHT expert panel (ClinVar variation ID 91366) and reported in 24 clinical laboratories as Pathogenic. It is a well-characterized founder mutation prevalent in Europe and North America, originally described by Clendenning et al. (2006) and extensively phenotyped by Senter et al. (2008) in 12 probands with Lynch syndrome-associated tumors showing isolated PMS2 loss by IHC.

Final determination: Rule4 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 Pathogenic.

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	Met	NM_000535.7:c.736_741delinsTGTGTGTGAAG is a frameshift indel in exon 7 introducing a premature termination codon at codon 248 (p.Pro246CysfsTer3). Under InSiGHT PMS2 VCEP v2.0.0, nonsense/frameshift variants introducing a PTC at codon ≤798 meet PVS1 at Very Strong strength. The PTC at codon 248 falls well within this boundary.	cspec pvs1_gene_context pvs1_variant_assessment
PS1	N/A	PS1 under InSiGHT PMS2 VCEP v2.0.0 applies to predicted missense substitutions sharing the same amino acid change as a known pathogenic variant, or non-canonical splice site variants with comparable splicing prediction. This variant is a frameshift indel, not a missense substitution or splice variant.
PS2	Not met	No de novo occurrence data were identified for this variant. PS2 under InSiGHT PMS2 VCEP v2.0.0 requires documented de novo points (0.5–≥4) in a proband with an MMR-deficient LS-spectrum tumor and confirmed maternity/paternity.
PS3	Not met	No calibrated functional assay data with functional odds for pathogenicity are available for this specific variant. OncoKB classifies the variant as Likely Oncogenic based on curated literature, but the cited functional studies (PMID:10439048, PMID:10874005, PMID:12697830) are gene-level (PMS2 knockout mouse models, MutLα dimerization) and do not report variant-specific functional assays.
PS4	N/A	PS4 is listed as Not Applicable under InSiGHT PMS2 VCEP v2.0.0.	cspec
PS5	Not assessed	No evidence available to evaluate PS5 (variant found by an established reputable source but with no independent evidence available in this case packet).
PM1	N/A	PM1 is listed as Not Applicable under InSiGHT PMS2 VCEP v2.0.0.	cspec
PM2	Met	This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0. Under InSiGHT PMS2 VCEP v2.0.0, PM2_Supporting is met when the allele frequency is <0.00002 (<1 in 50,000 alleles) in the gnomAD v4 dataset.	gnomad_v2 gnomad_v4 gnomad_canada
PM4	N/A	PM4 is listed as Not Applicable under InSiGHT PMS2 VCEP v2.0.0.	cspec
PM5	N/A	PM5 under InSiGHT PMS2 VCEP v2.0.0 applies only to missense changes at an amino acid residue where a different missense change has been classified as Pathogenic or Likely Pathogenic. This variant is a frameshift indel, not a missense change.
PM6	N/A	PM6 is listed as Not Applicable under InSiGHT PMS2 VCEP v2.0.0.	cspec
PP1	Not assessed	No co-segregation data (pedigrees with Bayes Likelihood Ratio) were available in the case materials to evaluate PP1.
PP2	N/A	PP2 is listed as Not Applicable under InSiGHT PMS2 VCEP v2.0.0.	cspec
PP3	Not met	PP3 under InSiGHT PMS2 VCEP v2.0.0 applies to missense variants with MAPP/PP2 Prior P score >0.68 or non-canonical splice variants with SpliceAI delta ≥0.2. This variant is a frameshift indel, not a missense substitution. Additionally, SpliceAI predicts no splicing impact (max delta score = 0.05), and no HCI prior score is available for non-substitution variants.	spliceai
PP4	Not assessed	No patient-specific tumor MSI or IHC data were available in the case materials to evaluate PP4. Published literature (PMID:18602922) reports that this variant was identified in probands selected by isolated PMS2 loss on IHC, with tumors showing MSI-H, satisfying at least PP4_Supporting in those individuals. However, without patient-specific data for the case under adjudication, PP4 cannot be formally applied.
PP5	Met	Expert panel International Society for Gastrointestinal Hereditary Tumours (InSiGHT) classified as Pathogenic.	cspec clinvar
BA1	Not met	BA1 under InSiGHT PMS2 VCEP v2.0.0 requires gnomAD v4 Grpmax filtering allele frequency ≥0.0028 (0.28%). This variant is absent from all gnomAD population databases. BA1 is not met.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	BS1 under InSiGHT PMS2 VCEP v2.0.0 requires gnomAD v4 Grpmax filtering allele frequency ≥0.00028 (0.028%). This variant is absent from all gnomAD population databases. BS1 is not met.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	BS2 under InSiGHT PMS2 VCEP v2.0.0 requires documented co-occurrence in trans with a known pathogenic PMS2 variant in a colorectal cancer patient diagnosed after age 45 without clinical manifestations of CMMRD. No such evidence was identified.
BS3	Not met	No calibrated functional assay data demonstrating functional odds for pathogenicity ≤0.48 or variant-specific proficient function are available. OncoKB labels the variant as Likely Oncogenic/Likely Loss-of-function, inconsistent with a benign functional readout.
BS4	Not met	No lack-of-segregation data available. BS4 requires combined Bayes Likelihood Ratio <0.48 from co-segregation analysis. No segregation evidence was provided in the case materials.
BP1	N/A	BP1 is listed as Not Applicable under InSiGHT PMS2 VCEP v2.0.0.	cspec
BP2	N/A	BP2 is listed as Not Applicable under InSiGHT PMS2 VCEP v2.0.0.	cspec
BP3	N/A	BP3 is listed as Not Applicable under InSiGHT PMS2 VCEP v2.0.0.	cspec
BP4	N/A	BP4 under InSiGHT PMS2 VCEP v2.0.0 applies to (a) missense variants with MAPP/PP2 Prior P score <0.11, or (b) intronic and synonymous variants with SpliceAI delta ≤0.1. This variant is a frameshift coding indel and does not fall within either category. BP4 is not applicable.
BP5	Not assessed	No patient-specific tumor data (MSS status, IHC results, BRAF V600E, or MLH1 methylation testing) were available in the case materials. Published data (PMID:18602922) notes BRAF V600E was identified in 2 of 47 tested probands with the c.736_741del6ins11 variant, but tumor context details (MSI-H status, MLH1 methylation) are not fully specified, precluding definitive BP5 application.
BP6	N/A	BP6 is listed as Not Applicable under InSiGHT PMS2 VCEP v2.0.0.	cspec
BP7	N/A	BP7 under InSiGHT PMS2 VCEP v2.0.0 applies to synonymous (silent) or intronic variants at or beyond -21/+7. This variant is a frameshift coding indel in exon 7 and does not fall within the scope of BP7.

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