Classification rationale

PVS1PM2 VUS

PMS2 c.73C>T nonsense · exon 2

VUS: PVS1 very strong applies because the nonsense variant truncates PMS2 at codon 25, within the VCEP threshold of codon 798 or earlier. VUS: PM2 supporting applies because the gnomAD v4.1 allele frequency is 6.20819e-07, below 0.00002.

PVS1 + PM2 → 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 · 2 applied · 11 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 · 2

Strength Supporting Moderate Strong Very strong

PVS1 very strong Pathogenic

Met, very strong: the PMS2 nonsense variant creates a premature stop at codon 25, within the VCEP threshold of codon 798 or earlier.

Case variant facts: NM_000535.7:c.73C>T, NP_000526.2:p.(Gln25Ter)/p.(Q25*), nonsense consequence, PMS2 exon 2.The VCEP PVS1 rule states: Nonsense/frameshift variant introducing Premature Termination Codon (PTC) ≤ codon 798 in PMS2. Refer to Appendix for details.VCEP-pilot-variants---MMR.xlsx.txt was searched for c.73C>T, p.Gln25Ter, and p.Q25*; the matching variant was not listed.

cspec ↗vcep_pvs1_decisiontree_mmr ↗vcep_vcep_pilot_variants_mmr ↗

PM2 supporting Pathogenic

Met at Supporting: gnomAD v4 total AF 6.20819e-07 is below 0.00002, with 1 allele in 1,610,776 and no homozygotes.

InSiGHT PMS2 VCEP CSPEC PM2 rule: absent/extremely rare allele frequency <0.00002 (<1 in 50,000 alleles) in the gnomAD v4 dataset.gnomAD v4.1 record for NM_000535.7:c.73C>T (p.Gln25Ter/p.Q25*): total AF 6.208187854797936e-07, 1/1610776 alleles, homozygotes 0; exome AC 1 and exome AN 1458496.VCEP-pilot-variants---MMR.xlsx.txt was searched for c.73C>T, p.Gln25Ter, p.Q25*, Q25*, and Q25Ter; no matching row was found.

cspec ↗gnomad_v4 ↗vcep_vcep_pilot_variants_mmr ↗

Assessed · not applied · 0 not met · 11 not assessed

Pathogenic

PS2 Not assessed: no proband-specific de novo finding, parental testing, or VCEP de novo point total is available for this variant.

PS3 Not assessed: no variant-specific functional assay result is available to compare with the VCEP's calibrated assay criteria or functional-assay flowchart.

PM3 Not assessed: no affected-proband observation, pathogenic PMS2 allele, or confirmed trans/cis phase is documented to generate a PM3 point total.

PP1 Not assessed: no variant-specific pedigree, relative genotypes, meioses, or combined Bayes Likelihood Ratio is available for PP1.

PP4 Not assessed: no patient-specific MSI, tumor-genome, or PMS2 IHC result is available to compare with the VCEP PP4 tumor-evidence rule.

Benign

BA1 Not assessed: gnomAD v4 total AF is 6.20819e-07, but the VCEP requires a Grpmax filtering AF, which is unavailable.

BS1 Not assessed: gnomAD v4 total AF is 6.20819e-07, but the VCEP requires a Grpmax filtering AF, which is unavailable.

BS2 Not assessed: no qualifying in-trans co-occurrence, cancer-age, CMMRD-exclusion, or phase-confirmation evidence is available.

BS3 Not assessed: no variant-specific proficient-function result or calibrated functional odds are available for comparison with the VCEP BS3 thresholds.

BS4 Not assessed: no variant-specific non-segregation pedigree, relative data, meioses, or combined Bayes Likelihood Ratio is available for BS4.

BP5 Not assessed: no patient-specific MSS, MMR-protein, BRAF V600E, or MLH1-methylation tumor evidence is available for the BP5 alternate-basis rule.

N/A · 15 PS1 · PS4 · PM1 · PM4 · PM5 · PM6 · PP2 · PP3 · PP5 · BP1 · BP2 · BP3 · BP4 · BP6 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 6.20819e-07; MAF= 0.00006%, 1/1610776 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47604e-07; MAF= 0.00008%, 1/1179796 alleles, homozygotes = 0).

v2.1

Absent from gnomAD v2.1.

🇨🇦 CA

Not available in gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

6.2e-05% · 1 / 1,610,776
0 hom

European (non-Finnish)

1 / 1,179,796

8.5e-05%

+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

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 Pathogenic (4 clinical laboratories) and as Likely pathogenic (2 clinical laboratories). (ClinVarID = 492293)

ClinVar ↗

In silico

SpliceAI predicts possible splice impact for this variant (max delta score = 0.34). BayesDel score = 0.655873.

SpliceAI ↗

Functional Likely Oncogenic

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV56151812, n = 1 times).

Hotspots

This variant does not lie in a statistically significant 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 · 8 PMIDs not cited in assessment

10439048 ↗ Mice defective in the DNA mismatch gene PMS2 are hypersensitive to MNU induced thymic lymphoma and are partially protected by transgenic expression of human MGMT. ONCOKB

10874005 ↗ Mutagenesis in PMS2- and MSH2-deficient mice indicates differential protection from transversions and frameshifts. ONCOKB

12697830 ↗ Dimerization of MLH1 and PMS2 limits nuclear localization of MutLalpha. ONCOKB

16144131 ↗ Two PMS2 mutations in a Turcot syndrome family with small bowel cancers. ONCOKB

20487569 ↗ MSH6 and PMS2 mutation positive Australian Lynch syndrome families: novel mutations, cancer risk and age of diagnosis of colorectal cancer. ONCOKB

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

20301390 ↗ Lynch Syndrome. CLINVAR

25856668 ↗ PMS2 monoallelic mutation carriers: the known unknown. CLINVAR

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