Classification rationale

BP4 VUS

PMS2 c.241G>A

The PMS2 c.241G>A (p.Glu81Lys, p.E81K) variant has been reported in ClinVar predominantly as a variant of uncertain significance, with one benign submission and no expert panel classification.¹ This variant is present in population databases, including gnomAD v4.1 at AF 0.0000326 (52/1,593,986 alleles) and gnomAD v2.1 at AF 0.0000159 (4/250,820 alleles); the gnomAD v4.1 frequency is above the PMS2 PM2 threshold of <0.00002 and below the BS1 and BA1 thresholds.² For PMS2 missense variants, the HCI prior is the primary computational metric; this variant has an HCI prior probability of 0.0446, which is below the BP4 threshold of <0.11 and supports BP4_Supporting, while SpliceAI predicts no splice impact with a max delta score of 0.00.³

BP4 → VUS

1 clinvar ↗

2 gnomad_v4 ↗gnomad_v2 ↗cspec ↗

3 hci_priorspliceai ↗revelbayesdelcspec ↗

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 · 16 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

For PMS2 missense variants, the VCEP prioritizes the HCI prior. This variant has an HCI prior probability of 0.0446, which is below the BP4 threshold of <0.11, supporting benign computational evidence. SpliceAI also predicts no splice impact with a max delta score of 0.00.

HCI prior probability 0.0446SpliceAI max delta score 0.00REVEL 0.516

cspec ↗spliceai ↗

Assessed · not applied · 7 not met · 9 not assessed

Pathogenic

PVS1 This variant is a missense substitution, p.(Glu81Lys), and does not fall into the PMS2 VCEP loss-of-function categories for PVS1.

PS1 No evidence was identified that a different nucleotide change causing the same p.(Glu81Lys) amino acid substitution has already been established by the PMS2 VCEP as Pathogenic or Likely Pathogenic.

PS2 No confirmed de novo occurrence with the tumor and parental-testing requirements needed for PMS2 PS2 was identified.

PS3 No validated PMS2 functional assay result for p.(Glu81Lys) was identified that would support a damaging effect under the PMS2 VCEP functional framework.

PM2 This variant is present in gnomAD v4.1 at AF 0.0000326 (52/1,593,986 alleles), which is above the PMS2 PM2 threshold of <0.00002, so PM2_Supporting is not met.

PM3 No phase-confirmed observation of this variant in trans with a pathogenic PMS2 variant in a constitutional mismatch repair deficiency context was identified.

PM5 No qualifying same-residue pathogenic or likely pathogenic missense comparator was identified for codon 81, and this variant also lacks the PP3 support required before applying PMS2 PM5.

PP1 No informative segregation data were identified for this variant, so the PMS2 PP1 Bayes likelihood ratio thresholds cannot be evaluated.

PP3 For PMS2 missense variants, the VCEP prioritizes the HCI prior.

PP4 No tumor microsatellite instability or immunohistochemistry evidence was identified to determine whether the clinical and tumor features meet the PMS2 PP4 thresholds.

Benign

BA1 The gnomAD v4.1 grpmax filtering allele frequency is 0.0000901, which is below the PMS2 BA1 threshold of 0.0028, so BA1 is not met.

BS1 The gnomAD v4.1 highest observed population frequency is 0.000225 and the grpmax filtering allele frequency is 0.0000901, both below the PMS2 BS1 threshold of 0.00028, so BS1 is not met.

BS2 No confirmed in-trans co-occurrence with a known pathogenic PMS2 variant in an individual meeting the PMS2 BS2 clinical requirements was identified.

BS3 No validated variant-specific functional study was identified showing retained PMS2 function or normal RNA behavior that would support BS3.

BS4 No informative family data were identified to show lack of segregation with disease, so BS4 cannot be evaluated.

BP5 No tumor phenotype data were identified to determine whether observed tumor features are inconsistent with a germline PMS2 explanation under the PMS2 BP5 rule.

N/A · 11 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= 3.26226e-05; MAF= 0.00326%, 52/1593986 alleles, homozygotes = 0) and has highest observed frequency in the Middle Eastern population (AF= 0.000225225; MAF= 0.02252%, 1/4440 alleles, homozygotes = 0); grpmax FAF= 9.008e-05.

v2.1

This variant is present in gnomAD v2.1 (AF= 1.59477e-05; MAF= 0.00159%, 4/250820 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.00016372; MAF= 0.01637%, 1/6108 alleles, homozygotes = 0); grpmax FAF= 2.93e-06.

🇨🇦 CA

This variant is present in gnomAD-Canada v1.0 (AF= 0.000108601; MAF= 0.01086%, 2/18416 alleles, homozygotes = 0) and has highest observed frequency in the amr population (AF= 0.00238663; grpmax FAF95= 0.00042326).

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.0033% · 52 / 1,593,986
0 hom · FAF 0.009%

Middle Eastern 1 / 4,440	0.023%
Admixed American 10 / 59,928	0.017%
East Asian 2 / 44,782	0.0045%
European (non-Finnish) 37 / 1,163,708	0.0032%
Remaining individuals 1 / 61,684	0.0016%
African/African American 1 / 74,450	0.0013%

+ 4 not observed (European (Finnish), Amish, South Asian, Ashkenazi Jewish)

gnomAD v2.1

0.0016% · 4 / 250,820
0 hom · FAF 0.00029%

Remaining individuals 1 / 6,108	0.016%
Admixed American 1 / 34,578	0.0029%
European (non-Finnish) 2 / 113,300	0.0018%

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

gnomAD Canada 🇨🇦

0.011% · 2 / 18,416
0 hom · FAF 0.042%

Latino/Admixed American

2 / 838

0.24%

+ 8 not observed (African/African American, Ashkenazi Jewish, East Asian, European (Finnish), Middle Eastern, European (non-Finnish), Remaining individuals, South Asian)

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) and as Uncertain Significance (1 clinical laboratory). (ClinVarID = 182817)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.516. BayesDel score = 0.0236541. HCI prior probability for pathogenicity = 0.0446. MAPP score = 3.49. Custom PP2 score = 0.774.

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; COSV56222918, 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 · 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

26552419 ↗ Combined Microsatellite Instability, MLH1 Methylation Analysis, and Immunohistochemistry for Lynch Syndrome Screening in Endometrial Cancers From GOG210: An NRG Oncology and Gynecologic Oncology Group Study. CLINVAR

31992580 ↗ Characterisation of heterozygous PMS2 variants in French patients with Lynch syndrome. CLINVAR

37894291 ↗ DNA Mismatch Repair Gene Variant Classification: Evaluating the Utility of Somatic Mutations and Mismatch Repair Deficient Colonic Crypts and Endometrial Glands. CLINVAR

11598466 ↗ Practice parameters for the identification and testing of patients at risk for dominantly inherited colorectal cancer--supporting documentation. CLINVAR

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

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

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