Variant classification summary

NM_000535.7:c.682G>A

PMS2 · NP_000526.2:p.(Gly228Ser) · NM_000535.7

GRCh37: chr7:6038762 C>T · GRCh38: chr7:5999131 C>T

Gene: PMS2 Transcript: NM_000535.7

Final call

VUS

BP4 supporting

Variant details

Gene

PMS2

Transcript

NM_000535.7

Protein

NP_000526.2:p.(Gly228Ser)

gnomAD AF

5.018705520947829e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

BP4 supporting: the MAPP/PP2 prior is 0.0077, below the PMS2 VCEP benign threshold.

2

VUS: no PMS2 VCEP pathogenic or benign combination rule is satisfied.

Final determination: Because BP4 supporting is the only applied criterion and no ClinGen InSiGHT PMS2 Version 2.0 criteria-combination rule matches, the final classification is VUS.

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	Not met	Not met: c.682G>A is a missense variant encoding p.(Gly228Ser) at codon 228, not a PMS2 nonsense, frameshift, canonical splice, or qualifying aberrant-splicing variant.	cspec
PS1	Not met	Not met: p.Gly228Ser is reported for c.682G>A, but no different-nucleotide p.Gly228Ser comparator established as Pathogenic by the VCEP was identified.	cspec PMID:31433215
PS2	Not assessed	Not assessed: one reported proband lacks documented parental testing or confirmed de novo status needed to assign de novo points.	cspec PMID:31433215
PS3	Not assessed	Not assessed: no variant-specific validated functional assay or calibrated functional odds are reported for p.Gly228Ser under the PMS2 VCEP requirements.	cspec vcep_functional_assay_flowchart PMID:31433215
PS4	N/A	Not applicable: the governing PMS2 InSiGHT VCEP specification explicitly marks PS4 as not applicable.	cspec
PM1	N/A	Not applicable: the governing PMS2 VCEP explicitly designates PM1 as Not Applicable, and no PMS2 domain-table entry is present.	cspec vcep_mmr_functional_domains
PM2	Not met	Not met: gnomAD v4.1 total allele frequency is 0.0000501871, above the PMS2 VCEP PM2 threshold of 0.00002.	cspec gnomad_v4 PMID:31433215
PM3	Not assessed	Not assessed: one proband was reported, but no pathogenic PMS2 partner variant, phase, or CMMRD-compatible clinical evidence was documented for the VCEP PM3 point system.	cspec PMID:31433215
PM4	N/A	Not applicable: the PMS2 VCEP designates PM4 as not applicable, and p.(Gly228Ser) causes no protein-length change.	cspec
PM5	Not met	Not met: the same-residue search found 0 comparator variants at PMS2 residue 228 satisfying the VCEP PM5 requirement.	cspec pm5_candidates
PM6	N/A	Not applicable: the PMS2 VCEP specification explicitly marks PM6 as not applicable for this gene framework.	cspec PMID:31433215
PP1	Not assessed	Not assessed: one reported proband has no pedigree segregation data or combined Bayes likelihood ratio for comparison with the VCEP thresholds.	cspec PMID:31433215
PP2	N/A	Not applicable: the governing PMS2 VCEP explicitly designates PP2 as Not Applicable for this gene.	cspec
PP3	Not met	Not met: HCI MAPP/PP2 Prior P is 0.0077, below the VCEP PP3 Supporting threshold of >0.68.	hci_prior vcep_hci_priors_pms2 cspec
PP4	Not met	Not met: the exact-variant report documents one proband, but MSI and immunohistochemistry were both not determined rather than showing qualifying PP4 phenotype evidence.	cspec PMID:31433215
PP5	Not met	Not met: ClinVar has zero exact-variant Expert Panel submissions, and the available single-submitter classifications are not qualifying Pathogenic or Likely Pathogenic assertions.	clinvar cspec
BA1	Not met	Not met: gnomAD v4.1 grpmax filtering allele frequency is 0.00006237, below the VCEP BA1 threshold of 0.0028.	cspec gnomad_v4
BS1	Not met	Not met: gnomAD v4.1 grpmax filtering allele frequency is 0.00006237, below the VCEP BS1 lower threshold of 0.00028.	cspec gnomad_v4
BS2	Not assessed	Not assessed: gnomAD v4.1 shows zero homozygotes, but no qualifying in-trans pathogenic variant, confirmed phase, and clinical context are documented for the VCEP BS2 rule.	cspec gnomad_v4
BS3	Not assessed	Not assessed: no variant-specific proficient functional assay or calibrated benign functional odds are reported for p.Gly228Ser under the PMS2 VCEP requirements.	cspec vcep_functional_assay_flowchart PMID:31433215
BS4	Not assessed	Not assessed: no tested relatives or combined Bayes likelihood ratio is available to demonstrate lack of cosegregation against the VCEP thresholds.	cspec PMID:31433215
BP1	N/A	Not applicable: the governing PMS2 VCEP explicitly designates BP1 as Not Applicable for this gene.	cspec
BP2	N/A	Not applicable: the PMS2 VCEP specification explicitly designates BP2 as not applicable.	cspec
BP3	N/A	Not applicable: the PMS2 VCEP designates BP3 as not applicable, and c.682G>A is a missense substitution rather than a repeat-region in-frame indel.	cspec
BP4	Met	Met, Supporting: HCI MAPP/PP2 Prior P is 0.0077, below the VCEP BP4 threshold of <0.11.	hci_prior vcep_hci_priors_pms2 cspec
BP5	Not met	Not met: one exact-variant proband was reported, but no qualifying MSS, retained MMR protein, BRAF V600E, or MLH1-methylation tumor result was documented.	cspec PMID:31433215
BP6	Not met	Not met: the only exact-variant Benign ClinVar assertion is from a single laboratory, with zero Expert Panel submissions and no qualifying Likely Benign or Benign Expert Panel classification.	clinvar cspec
BP7	N/A	Not applicable: c.682G>A is a missense variant producing p.Gly228Ser, not a synonymous or qualifying intronic variant.	cspec

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