LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-10-05
Case ID: NM_000535.7_c.1567T_A_20261005_182812
Framework: ACMG/AMP 2015
Variant classification summary

NM_000535.7:c.1567T>A

PMS2  · NP_000526.2:p.(Ser523Thr)  · NM_000535.7
GRCh37: chr7:6026829 A>T  ·  GRCh38: chr7:5987198 A>T
Gene: PMS2 Transcript: NM_000535.7
Final call
Likely Benign
BS1 strong BP4 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
PMS2
Transcript
NM_000535.7
Protein
NP_000526.2:p.(Ser523Thr)
gnomAD AF
0.00016730407453582414 (v4.1)
ClinVar
Likely benign
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
Likely Benign: BS1 (strong) - gnomAD v4.1 grpmax filtering allele frequency 0.00045665 falls within the PMS2 VCEP BS1 range.
2
Likely Benign: BP4 (supporting) - the PMS2 VCEP HCI prior probability is 0.0008, below the <0.11 cutoff.
Final determination: Under Rule18 of the PMS2 InSiGHT VCEP Version 2.0 criteria-combination framework, one Benign Strong criterion plus one Benign Supporting criterion yields Likely Benign.
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 Not applicable: NM_000535.7:c.1567T>A is a missense variant, p.Ser523Thr, not a specified PMS2 loss-of-function or qualifying splice-altering class.
cspec vcep_pvs1_decisiontree_mmr
PS1 Not met Not met: the only reported alternate-nucleotide Ser523Thr observation was not established as Pathogenic by the PMS2 VCEP.
cspec PMID:17016615
PS2 Not assessed Not assessed: no proband-level parental testing, de novo confirmation, LS-spectrum tumor, or tumor MSI/IHC evidence is available to assign VCEP de novo points.
cspec
PS3 Not assessed Not assessed: no variant-specific functional assay or calibrated functional odds are reported for PMS2 p.Ser523Thr.
cspec oncokb PMID:22290698
PS4 N/A Not applicable: the PMS2 VCEP explicitly excludes PS4 proband-counting evidence because tumor IHC is evaluated through PP4.
cspec
PM1 N/A Not applicable: the governing PMS2 VCEP designates PM1 as Not Applicable, and no authoritative domain-table entry is present.
cspec vcep_mmr_functional_domains
PM2 Not met Not met: gnomAD v4.1 overall AF is 0.000167304, above the PMS2 VCEP PM2 threshold of less than 0.00002.
cspec gnomad_v4
PM3 Not assessed Not assessed: no affected-proband, homozygous, or phase-resolved in-trans pathogenic PMS2 observation is documented to assign VCEP PM3 points.
cspec PMID:26232782 PMID:22290698
PM4 N/A Not applicable: the PMS2 VCEP explicitly designates PM4 as not applicable, and c.1567T>A produces only the amino-acid substitution p.Ser523Thr.
cspec
PM5 Not met Not met: zero qualifying Pathogenic or Likely Pathogenic same-residue comparators were identified for Ser523.
cspec pm5_candidates
PM6 N/A Not applicable: the governing PMS2 InSiGHT VCEP version 2.0 explicitly designates PM6 as not applicable.
cspec
PP1 Not assessed Not assessed: no pedigree, informative meioses, phenotype-linked genotypes, or combined Bayes likelihood ratio is reported for PP1 evaluation.
cspec
PP2 N/A Not applicable: the governing PMS2 VCEP explicitly designates PP2 as Not Applicable.
cspec
PP3 Not met Not met: the governing PMS2 HCI prior probability is 0.0008, below the VCEP PP3 Supporting threshold of >0.68.
cspec vcep_hci_priors_pms2 revel
PP4 Not assessed Not assessed: no case-specific CRC/endometrial tumor count or qualifying MSI-H and PMS2-consistent protein-loss result is available for the PP4 thresholds.
cspec PMID:26232782
PP5 N/A Not applicable: the PMS2 VCEP excludes PP5, and ClinVar has no exact-variant expert-panel Pathogenic or Likely pathogenic classification.
cspec clinvar
BA1 Not met Not met: gnomAD v4.1 grpmax FAF is 0.00045665, below the PMS2 VCEP BA1 threshold of 0.0028.
cspec gnomad_v4
BS1 Met Met, Strong: gnomAD v4.1 grpmax FAF is 0.00045665, within the PMS2 VCEP BS1 range of 0.00028 to less than 0.0028.
cspec gnomad_v4
BS2 Not assessed Not assessed: no qualifying in-trans pathogenic variant, age-specific cancer phenotype, CMMRD assessment, or confirmed phase data are available.
cspec
BS3 Not assessed Not assessed: no variant-specific protein, RNA, MMR activity, or calibrated functional assay demonstrates proficient function for p.Ser523Thr.
cspec oncokb PMID:22290698
BS4 Not assessed Not assessed: no non-segregating affected relative, informative pedigree data, or combined Bayes likelihood ratio is reported for BS4 evaluation.
cspec
BP1 N/A Not applicable: the governing PMS2 VCEP explicitly designates BP1 as Not Applicable.
cspec
BP2 N/A Not applicable: the PMS2 VCEP v2.0 explicitly designates BP2 as not applicable.
cspec
BP3 N/A Not applicable: the PMS2 VCEP designates BP3 as not applicable, and this SNV causes p.Ser523Thr rather than an in-frame repeat-region indel.
cspec
BP4 Met Met, Supporting: the governing PMS2 HCI prior probability is 0.0008, below the VCEP BP4 cutoff of <0.11.
cspec vcep_hci_priors_pms2
BP5 Not assessed Not assessed: no case-specific MSS, MMR-protein, BRAF V600E, or MLH1-methylation findings are available for the BP5 tumor-count thresholds.
cspec
BP6 N/A Not applicable: the PMS2 VCEP excludes BP6, and ClinVar has no exact-variant expert-panel Benign or Likely benign classification.
cspec clinvar
BP7 N/A Not applicable: PMS2 c.1567T>A is a missense SNV encoding p.S523T, not a synonymous or qualifying intronic variant.
cspec
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