Classification rationale

BP4 VUS

PMS2 c.1501G>A missense · exon 11

BP4 Supporting: the PMS2 HCI prior pathogenicity probability is 0.002, below the VCEP BP4 threshold of <0.11.

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 · 15 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 prior pathogenicity probability 0.002 is below the PMS2 VCEP BP4 threshold of <0.11.

The PMS2 VCEP index declares HCI-PRIORS-PMS2.txt governing for PP3 and BP4 in missense variants.The exact HCI table entry for c.1501G>A / p.V501M assigns pathogenicity probability 0.002.The PMS2 VCEP specification assigns BP4 Supporting to a missense variant with MAPP/PP2 Prior P <0.11; 0.002 satisfies this rule.

cspec ↗

Assessed · not applied · 6 not met · 9 not assessed

Pathogenic

PS1 Not met: no alternate-nucleotide PMS2 variant encoding p.Val501Met is established by the VCEP as Pathogenic.

PS2 Not assessed: no proband-specific de novo observation, parental confirmation, LS-spectrum tumor evidence, or de novo point total is documented.

PS3 Not assessed: no variant-specific PMS2 functional assay result or calibrated functional odds are available to meet the VCEP PS3 thresholds of >2.08, >4.3, or >18.7.

PM2 Not met: gnomAD v4.1 allele frequency is 5.6378237256969525e-05, exceeding the PMS2 PM2 threshold of 0.00002.

PM3 Not assessed: no affected-proband observation documents a second pathogenic PMS2 variant in trans or provides phase evidence needed for PM3 points.

PM5 Not met: zero same-residue Val501 comparator candidates were found, and the HCI prior probability is 0.002 versus the >0.68 PP3-supporting threshold.

PP1 Not assessed: no tested relatives, pedigree segregation data, meioses, or combined Bayes likelihood ratio is documented.

PP3 Not met: HCI prior pathogenicity probability 0.002 is below the PMS2 VCEP PP3 supporting threshold of >0.68.

PP4 Not assessed: no variant-specific MSI, tumor-genome, or PMS2-consistent IHC result is available to compare with the VCEP's one-tumor PP4 threshold.

Benign

BA1 Not met: gnomAD v4.1 grpmax filtering allele frequency is 5.628e-05, below the PMS2 BA1 threshold of 0.0028.

BS1 Not met: gnomAD v4.1 grpmax filtering allele frequency is 5.628e-05, below the PMS2 BS1 lower threshold of 0.00028.

BS2 Not assessed: gnomAD v4.1 shows zero homozygotes, but the PMS2 BS2 rule requires documented in-trans clinical co-occurrence and confirmed phase.

BS3 Not assessed: no variant-specific proficient assay result or calibrated functional odds are available to meet the VCEP BS3 thresholds of <=0.05 or >0.05 and <=0.48.

BS4 Not assessed: no non-segregating affected relatives, pedigree analysis, or combined Bayes likelihood ratio is documented.

BP5 Not assessed: no qualifying tumor phenotype, BRAF V600E, or MLH1 methylation result is available for comparison with the BP5 tumor-count thresholds.

N/A · 12 PVS1 · PS4 · PM1 · PM4 · PM6 · PP2 · PP5 · BP1 · BP2 · BP3 · BP6 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 5.63782e-05; MAF= 0.00564%, 91/1614098 alleles, homozygotes = 0) and has highest observed frequency in the Middle Eastern population (AF= 0.000164962; MAF= 0.01650%, 1/6062 alleles, homozygotes = 0); grpmax FAF= 5.628e-05.

v2.1

This variant is present in gnomAD v2.1 (AF= 3.97801e-05; MAF= 0.00398%, 10/251382 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000163079; MAF= 0.01631%, 1/6132 alleles, homozygotes = 0); grpmax FAF= 3.419e-05.

🇨🇦 CA

Not available in gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.0056% · 91 / 1,614,098
0 hom · FAF 0.0056%

Middle Eastern 1 / 6,062	0.016%
Remaining individuals 8 / 62,512	0.013%
European (non-Finnish) 81 / 1,180,022	0.0069%
East Asian 1 / 44,880	0.0022%

+ 6 not observed (Admixed American, European (Finnish), Amish, South Asian, Ashkenazi Jewish, African/African American)

gnomAD v2.1

0.004% · 10 / 251,382
0 hom · FAF 0.0034%

Remaining individuals 1 / 6,132	0.016%
European (non-Finnish) 8 / 113,710	0.007%
East Asian 1 / 18,394	0.0054%

+ 5 not observed (African/African American, Admixed American, Ashkenazi Jewish, European (Finnish), South Asian)

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 (8 clinical laboratories) and as Likely benign (3 clinical laboratories) and as Benign (1 clinical laboratory). (ClinVarID = 127762)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.07. BayesDel score = -0.530405. HCI prior probability for pathogenicity = 0.002. MAPP score = 3.75. Custom PP2 score = 0.001.

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

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; COSV56223549, n = 2 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

15604628 ↗ Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors. CLINVAR

20301390 ↗ Lynch Syndrome. CLINVAR

23535968 ↗ Informing family members of individuals with Lynch syndrome: a guideline for cli CLINVAR

25356965 ↗ ACMG policy statement: updated recommendations regarding analysis and reporting CLINVAR

25741868 ↗ Standards and guidelines for the interpretation of sequence variants: a joint co CLINVAR

26467025 ↗ A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mende CLINVAR

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

28577310 ↗ Elucidating the molecular basis of MSH2-deficient tumors by combined germline and somatic analysis. CLINVAR

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