Classification rationale

BP4 VUS

PMS2 c.682G>A missense · exon 6

BP4 supporting: the MAPP/PP2 prior is 0.0077, below the PMS2 VCEP benign threshold. VUS: no PMS2 VCEP pathogenic or benign combination rule is satisfied.

BP4 → VUS

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

Gene diagram · NM_000535.7 · variants mapped to exon structure

PMS2 NM_000535.7

Fetching transcript structure from UCSC…

Applied criteria · 1 applied · 18 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 1

Strength Supporting Moderate Strong Very strong

BP4 supporting Benign

Met, Supporting: HCI MAPP/PP2 Prior P is 0.0077, below the VCEP BP4 threshold of <0.11.

The PMS2 HCI prior table was searched for c.682G>A, p.Gly228Ser, and p.G228S; the exact c.682G>A / p.G228S entry was found.The exact HCI entry reports MAPP/PP2 Prior P = 0.0077.The governing PMS2 VCEP specifies BP4 Supporting for a missense variant with MAPP/PP2 Prior P <0.11; the observed 0.0077 satisfies this threshold.

cspec ↗

Assessed · not applied · 11 not met · 7 not assessed

Pathogenic

PVS1 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.

PS1 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.

PS2 Not assessed: one reported proband lacks documented parental testing or confirmed de novo status needed to assign de novo points.

PS3 Not assessed: no variant-specific validated functional assay or calibrated functional odds are reported for p.Gly228Ser under the PMS2 VCEP requirements.

PM2 Not met: gnomAD v4.1 total allele frequency is 0.0000501871, above the PMS2 VCEP PM2 threshold of 0.00002.

PM3 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.

PM5 Not met: the same-residue search found 0 comparator variants at PMS2 residue 228 satisfying the VCEP PM5 requirement.

PP1 Not assessed: one reported proband has no pedigree segregation data or combined Bayes likelihood ratio for comparison with the VCEP thresholds.

PP3 Not met: HCI MAPP/PP2 Prior P is 0.0077, below the VCEP PP3 Supporting threshold of >0.68.

PP4 Not met: the exact-variant report documents one proband, but MSI and immunohistochemistry were both not determined rather than showing qualifying PP4 phenotype evidence.

PP5 Not met: ClinVar has zero exact-variant Expert Panel submissions, and the available single-submitter classifications are not qualifying Pathogenic or Likely Pathogenic assertions.

Benign

BA1 Not met: gnomAD v4.1 grpmax filtering allele frequency is 0.00006237, below the VCEP BA1 threshold of 0.0028.

BS1 Not met: gnomAD v4.1 grpmax filtering allele frequency is 0.00006237, below the VCEP BS1 lower threshold of 0.00028.

BS2 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.

BS3 Not assessed: no variant-specific proficient functional assay or calibrated benign functional odds are reported for p.Gly228Ser under the PMS2 VCEP requirements.

BS4 Not assessed: no tested relatives or combined Bayes likelihood ratio is available to demonstrate lack of cosegregation against the VCEP thresholds.

BP5 Not met: one exact-variant proband was reported, but no qualifying MSS, retained MMR protein, BRAF V600E, or MLH1-methylation tumor result was documented.

BP6 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.

N/A · 9 PS4 · PM1 · PM4 · PM6 · PP2 · BP1 · BP2 · BP3 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 5.01871e-05; MAF= 0.00502%, 81/1613962 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000120179; MAF= 0.01202%, 9/74888 alleles, homozygotes = 0); grpmax FAF= 6.237e-05.

v2.1

This variant is present in gnomAD v2.1 (AF= 3.5787e-05; MAF= 0.00358%, 9/251488 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000123031; MAF= 0.01230%, 2/16256 alleles, homozygotes = 0); grpmax FAF= 2.132e-05.

🇨🇦 CA

Not available in gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.005% · 81 / 1,613,962
0 hom · FAF 0.0062%

African/African American 9 / 74,888	0.012%
European (non-Finnish) 66 / 1,180,036	0.0056%
Remaining individuals 2 / 62,482	0.0032%
East Asian 1 / 44,896	0.0022%
South Asian 2 / 91,084	0.0022%
Admixed American 1 / 59,964	0.0017%

+ 4 not observed (European (Finnish), Amish, Middle Eastern, Ashkenazi Jewish)

gnomAD v2.1

0.0036% · 9 / 251,488
0 hom · FAF 0.0021%

African/African American 2 / 16,256	0.012%
South Asian 2 / 30,616	0.0065%
European (non-Finnish) 4 / 113,762	0.0035%
Admixed American 1 / 34,592	0.0029%

+ 4 not observed (Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals)

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Uncertain significance (13 clinical laboratories) and as Benign (1 clinical laboratory). (ClinVarID = 127794)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.16). REVEL score = 0.466. BayesDel score = 0.0576274. HCI prior probability for pathogenicity = 0.0077. MAPP score = 1.17. Custom PP2 score = 0.936.

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. PMS2, an endonuclease involved in DNA repair, is altered in various cancers.

OncoKB ↗

COSMIC

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant has previously been reported in somatic cancers (COSMIC; COSV105851171, n = 1 times).

Hotspots

This variant does not lie in a statistically significant cancer hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

9Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 9 PMIDs not cited in assessment

25070057 ↗ Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the US Multi-society Task Force on colorectal cancer. CLINVAR

25741868 ↗ Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. CLINVAR

26467025 ↗ A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders. CLINVAR

27882345 ↗ Institutional implementation of clinical tumor profiling on an unselected cancer population. CLINVAR

31391288 ↗ Tumour characteristics provide evidence for germline mismatch repair missense variant pathogenicity. CLINVAR

31433215 ↗ Detection of PMS2 Mutations by Screening Hereditary Nonpolyposis Colon Cancer Families from Denmark and Sweden. CLINVAR

31672839 ↗ Management of patients with increased risk for familial pancreatic cancer: updated recommendations from the International Cancer of the Pancreas Screening (CAPS) Consortium. CLINVAR

33193653 ↗ New Pathogenic Germline Variants in Very Early Onset and Familial Colorectal Cancer Patients. CLINVAR

28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR

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