LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-07-13
Case ID: NM_000535.7_c.2380C_T_20260713_175541
Framework: ACMG/AMP 2015
Variant classification summary

NM_000535.7:c.2380C>T

PMS2  · NP_000526.2:p.(Pro794Ser)  · NM_000535.7
GRCh37: chr7:6017284 G>A  ·  GRCh38: chr7:5977653 G>A
Gene: PMS2 Transcript: NM_000535.7
Final call
VUS
PM2 supporting PP3 moderate
All criteria require review: For research and educational purposes only.
Variant details
Gene
PMS2
Transcript
NM_000535.7
Protein
NP_000526.2:p.(Pro794Ser)
gnomAD AF
3.116072452423806e-06 (v4.1)
ClinVar
Uncertain significance
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
NM_000535.7:c.2380C>T (p.Pro794Ser) is a missense variant in exon 14 of PMS2.
2
This variant is extremely rare in population databases: gnomAD v4.1 grpmax filtering allele frequency is 3.67e-06 (5/1,604,584 alleles), meeting the VCEP PM2_Supporting threshold of <0.00002.
3
The HCI prior probability for pathogenicity is 0.8253, exceeding the VCEP PP3_Moderate threshold of >0.81, supporting a deleterious computational prediction.
4
No functional studies, segregation data, tumor pathology data, or de novo observations are available for this variant. The variant is absent from COSMIC and OncoKB reports no variant-specific functional evidence.
5
In ClinVar, this variant is classified as Uncertain Significance by 12 clinical laboratories and as Benign by 1 laboratory (ClinVar ID 220740), with no expert panel classification.
6
Applying the ClinGen InSiGHT PMS2 VCEP v2.0.0 combining criteria: PM2_Supporting (1 point) and PP3_Moderate (2 points) are met. These do not reach any pathogenic classification tier (requires ≥1 Strong or ≥3 Moderate for Likely Pathogenic, or ≥2 Supporting for Likely Benign). The variant remains a Variant of Uncertain Significance.
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 2.0.0 v2.0.0 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 N/A NM_000535.7:c.2380C>T is a missense substitution (p.Pro794Ser). The ClinGen InSiGHT PMS2 VCEP v2.0.0 PVS1 rules are restricted to nonsense/frameshift variants introducing a premature termination codon, canonical ±1,2 splice variants, initiation codon variants, and large genomic alterations. A missense variant does not qualify for any PVS1 strength tier.
cspec
PS1 Not met PS1 requires the same amino acid change (p.Pro794Ser) from a different underlying nucleotide change previously classified as Pathogenic or Likely Pathogenic by this VCEP. No alternative nucleotide substitution producing p.Pro794Ser is known or has been classified by the InSiGHT PMS2 VCEP.
cspec
PS2 Not met PS2 requires de novo occurrence with confirmed maternity and paternity in a patient with MMR-deficient LS-spectrum tumor. No de novo observation has been reported for this variant.
PS3 Not met PS3 requires variant-specific functional evidence from calibrated assays with defined odds of pathogenicity. The VCEP Functional-assay-SVI-documentation-MMR spreadsheet contains no entry for p.Pro794Ser. No functional data exists for this variant in the literature.
PS4 N/A PS4 is marked Not Applicable by the ClinGen InSiGHT PMS2 VCEP v2.0.0.
cspec
PS5 Not assessed PS5 is not included in the ClinGen InSiGHT PMS2 VCEP v2.0.0 specification and is not in the assessment list.
PM1 N/A PM1 is marked Not Applicable by the ClinGen InSiGHT PMS2 VCEP v2.0.0.
cspec
PM2 Met The variant is extremely rare in population databases, meeting the VCEP PM2_Supporting threshold. In gnomAD v4.1, the grpmax filtering allele frequency is 3.67e-06 (5/1,604,584 alleles), well below the VCEP cutoff of <0.00002 (<1 in 50,000 alleles). One homozygote is observed in gnomAD v4.1, which may represent a technical artifact given the PMS2/PMS2CL pseudogene homology, but does not disqualify the allele frequency criterion.
gnomad_v4
PM5 Not met PM5 requires a different missense change at the same amino acid residue (codon 794) previously classified as Pathogenic or Likely Pathogenic by this VCEP, with PP3 also being met. No other missense variant at codon 794 has been classified as P/LP by the InSiGHT PMS2 VCEP, and no comparator candidates were identified in ClinVar.
cspec pm5_candidates
PM6 N/A PM6 is marked Not Applicable by the ClinGen InSiGHT PMS2 VCEP v2.0.0.
cspec
PP1 Not met PP1 requires co-segregation with disease in pedigrees with a combined Bayes Likelihood Ratio meeting VCEP thresholds. No co-segregation data are available for this variant.
PP2 N/A PP2 is marked Not Applicable by the ClinGen InSiGHT PMS2 VCEP v2.0.0.
cspec
PP3 Met The HCI prior probability for pathogenicity (MAPP/PP2 Prior P score) for c.2380C>T (p.Pro794Ser) is 0.8253, exceeding the VCEP PP3_Moderate threshold of >0.81. This in silico predictor, calibrated for PMS2 missense variants, supports a deleterious effect. SpliceAI predicts no splicing impact (max delta = 0.00), so the in silico evidence is limited to the amino acid substitution effect.
hci_prior spliceai
PP4 Not met PP4 requires MSI-H colorectal/endometrial tumors with loss of MMR protein expression consistent with PMS2. No tumor pathology data (MSI status, IHC) are available for carriers of this variant.
PP5 N/A PP5 is marked Not Applicable by the ClinGen InSiGHT PMS2 VCEP v2.0.0.
cspec
BA1 Not met BA1 requires gnomAD v4 grpmax filtering allele frequency ≥ 0.0028 (0.28%). The variant's grpmax FAF is 3.67e-06, far below this threshold.
gnomad_v4
BS1 Not met BS1 requires gnomAD v4 grpmax filtering allele frequency ≥ 0.00028 and < 0.0028. The variant's grpmax FAF is 3.67e-06, below the BS1 lower bound.
gnomad_v4
BS2 Not met BS2 requires co-occurrence in trans with a known pathogenic PMS2 variant in a CRC patient after age 45 without CMMRD features. No such co-occurrence data are available.
BS3 Not met BS3 requires calibrated functional assays demonstrating a benign effect (odds of pathogenicity ≤ 0.05 for BS3_Strong, or proficient function per the MMR functional assay flowchart for BS3_Supporting). No functional data exist for p.Pro794Ser.
BS4 Not met BS4 requires lack of co-segregation with disease in pedigrees meeting Bayes Likelihood Ratio thresholds. No segregation data are available.
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 is marked Not Applicable by the ClinGen InSiGHT PMS2 VCEP v2.0.0. Additionally, this is a missense variant, not an in-frame indel in a repetitive region.
cspec
BP4 Not met BP4_Supporting for missense variants requires an HCI prior probability < 0.11. The HCI prior for c.2380C>T is 0.8253, which does not meet the BP4 threshold. REVEL score is 0.543 and BayesDel is 0.027, neither providing strong benign evidence.
hci_prior revel bayesdel spliceai
BP5 Not met BP5 requires MSS colorectal/endometrial tumors and/or loss of MMR protein expression inconsistent with PMS2. No tumor pathology data are available.
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.2380C>T is a missense variant (p.Pro794Ser) and does not qualify.
cspec
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