LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-07-29
Case ID: NM_000535.6_c.1321G_T_20260729_092335
Framework: ACMG/AMP 2015
Variant classification summary

NM_000535.6:c.1321G>T

PMS2  · NP_000526.2:p.(Glu441Ter)  · NM_000535.6
GRCh37: chr7:6027075 C>A  ·  GRCh38: chr7:5987444 C>A
Gene: PMS2 Transcript: NM_000535.6
Final call
VUS
PVS1 very strong PM2 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
PMS2
Transcript
NM_000535.6
Protein
NP_000526.2:p.(Glu441Ter)
gnomAD AF
ClinVar
Pathogenic
OncoKB
Likely Oncogenic
Classification rationale
Interpretation summary
Generated evidence synthesis
1
NM_000535.6:c.1321G>T (p.Glu441Ter) is a nonsense variant in PMS2 exon 11 introducing a premature termination codon at position 441, which is well before the VCEP-defined PVS1 boundary at codon 798.
2
This variant meets PVS1 at Very Strong strength under the InSiGHT PMS2 VCEP v2.0 criteria for nonsense variants introducing a PTC ≤ codon 798.
3
The variant is absent from gnomAD v2.1 and v4.1 population databases (0 alleles), meeting PM2 at Supporting strength under VCEP criteria (<0.00002 allele frequency threshold).
4
No variant-specific functional data, de novo observations, cosegregation data, or tumor phenotype data were identified in the case materials or reviewed literature.
5
SpliceAI predicts no significant splice impact (max delta 0.03), confirming that the primary molecular consequence is protein truncation rather than aberrant splicing.
6
Under the InSiGHT PMS2 VCEP v2.0 combination rules, 1 Very Strong criterion (PVS1) plus 1 Supporting criterion (PM2) is sufficient for a Pathogenic classification (Rule 1 or Rule 4).
Final determination: No criteria-combination rule matched the adjudicated criteria 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 framework, so the variant remains a Variant of Uncertain Significance pending human review.
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 Nonsense variant NM_000535.6:c.1321G>T introduces a premature termination codon at position 441 (p.Glu441Ter), which is ≤ codon 798. Per InSiGHT PMS2 VCEP v2.0, nonsense/frameshift variants introducing a PTC ≤ codon 798 meet PVS1 at Very Strong strength.
cspec pvs1_generic_framework gnomad_v2 gnomad_v4
PS1 N/A PS1 in the PMS2 VCEP applies only to predicted missense substitutions encoding the same amino acid change as a previously established pathogenic variant. NM_000535.6:c.1321G>T is a nonsense variant (p.Glu441Ter), not a missense substitution.
cspec
PS2 Not met No de novo occurrence data for NM_000535.6:c.1321G>T is present in the case materials or literature reviewed. De novo points cannot be assigned without confirmed maternity and paternity in a proband with MMR-deficient LS-spectrum tumor.
PS3 Not met No variant-specific functional data exists for NM_000535.6:c.1321G>T (p.Glu441Ter). The reviewed literature includes general PMS2 functional studies (knockout mouse models, MMR biochemistry) but none tested this exact nonsense variant or a systematically characterized range that includes codon 441.
PS4 N/A PS4 is marked Not Applicable by the InSiGHT PMS2 VCEP v2.0.
cspec
PS5 N/A PS5 is not defined in the InSiGHT PMS2 VCEP v2.0 framework. Under VCEP framework precedence, criteria not specified by the expert panel are not applied. Additionally, this is a nonsense variant, making the generic PS5 criterion (same amino acid change as established pathogenic variant by different nucleotide change) inapplicable.
cspec
PM1 N/A PM1 is marked Not Applicable by the InSiGHT PMS2 VCEP v2.0.
cspec
PM2 Met NM_000535.6:c.1321G>T is absent from gnomAD v2.1 and v4.1 (0 alleles). Per PMS2 VCEP v2.0, absence or extremely rare allele frequency (<0.00002, <1 in 50,000 alleles) in gnomAD v4 meets PM2 at Supporting strength.
gnomad_v2 gnomad_v4 cspec
PM5 N/A PM5 in the PMS2 VCEP applies only to missense changes at an amino acid residue where a different missense change has been classified as Pathogenic/Likely Pathogenic. NM_000535.6:c.1321G>T is a nonsense variant (p.Glu441Ter) introducing a stop codon, not a missense change. The pm5_candidates.json confirms the variant is not missense-like.
cspec pm5_candidates
PM6 N/A PM6 is marked Not Applicable by the InSiGHT PMS2 VCEP v2.0.
cspec
PP1 Not met No cosegregation data is available for NM_000535.6:c.1321G>T. Cosegregation analysis requires pedigree data with combined Bayes Likelihood Ratio calculation; none was provided or identified in the case materials.
PP2 N/A PP2 is marked Not Applicable by the InSiGHT PMS2 VCEP v2.0.
cspec
PP3 N/A PP3 in the PMS2 VCEP applies only to missense variants with HCI MAPP/PP2 Prior P scores (>0.68 for Supporting, >0.81 for Moderate). This is a nonsense variant and HCI prior is not available. BayesDel score (0.297) is noted but does not trigger PP3 under the VCEP framework, which relies exclusively on the HCI prior calibration for in silico evidence.
cspec bayesdel vcep_hci_priors_pms2
PP4 Not met No tumor-specific MSI or IHC data is available for NM_000535.6:c.1321G>T carriers in the case materials. PP4 requires at least one CRC/endometrial MSI-H tumor with loss of PMS2 protein expression consistent with the variant location, or tumor genome data. While the PMS2 gene is associated with Lynch syndrome and loss of MMR function is the established disease mechanism, variant-level tumor phenotype data is absent.
oncokb
PP5 N/A PP5 is marked Not Applicable by the InSiGHT PMS2 VCEP v2.0.
cspec
BA1 Not met NM_000535.6:c.1321G>T is absent from gnomAD v4.1 (Grpmax filtering allele frequency = 0). The PMS2 VCEP BA1 threshold is ≥0.0028 (0.28%). This variant does not meet the stand-alone benign population frequency criterion.
gnomad_v4 cspec
BS1 Not met NM_000535.6:c.1321G>T is absent from gnomAD v4.1. The PMS2 VCEP BS1 threshold is ≥0.00028 and <0.0028 (0.028-0.28%). This variant is absent, not within the BS1 range.
gnomad_v4 cspec
BS2 Not met No evidence of co-occurrence in trans with a known pathogenic PMS2 variant in a patient with CRC after age 45 and no CMMRD features. BS2 requires confirmed phase (parental testing) showing trans configuration with a known pathogenic variant.
BS3 Not met No variant-specific functional data demonstrating proficient MMR function for NM_000535.6:c.1321G>T. The PMS2 VCEP BS3 requires calibrated functional assays with odds for pathogenicity ≤0.05, or variant-specific proficient function in protein/mRNA-based assays. No such data exists for this variant.
BS4 Not met No lack-of-cosegregation data is available. BS4 requires combined Bayes Likelihood Ratio <0.05 (Strong) or >0.05 and ≤0.48 (Supporting) from pedigree analysis. None was provided in the case materials.
BP1 N/A BP1 is marked Not Applicable by the InSiGHT PMS2 VCEP v2.0.
cspec
BP2 N/A BP2 is marked Not Applicable by the InSiGHT PMS2 VCEP v2.0.
cspec
BP4 N/A BP4 in the PMS2 VCEP applies only to missense variants with HCI MAPP/PP2 Prior P score <0.11, or intronic/synonymous variants with SpliceAI delta ≤0.1. This is a nonsense variant. SpliceAI max delta is 0.03 (no splicing impact predicted) but the VCEP BP4 rule does not extend to nonsense variants.
cspec spliceai vcep_hci_priors_pms2
BP5 Not met No tumor data showing MSS and/or retained PMS2 protein expression in variant carriers is available. BP5 requires ≥2 CRC/endometrial tumors with MSS and/or no loss of MMR expression, or BRAF V600E/MLH1 methylation in MSI-H tumors. No such evidence exists in the case materials.
BP6 N/A BP6 is marked Not Applicable by the InSiGHT PMS2 VCEP v2.0.
cspec
BP7 N/A BP7 in the PMS2 VCEP applies only to synonymous (silent) or intronic variants at or beyond -21/+7 positions. NM_000535.6:c.1321G>T is a nonsense variant producing a premature termination codon; BP7 is not applicable.
cspec
BP3 N/A Skipped per user instruction: trivially not applicable.
PM3 N/A Skipped per user instruction: trivially not applicable.
PM4 N/A Skipped per user instruction: trivially not applicable.
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