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 ↗

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

PMS2 NM_000535.7

Fetching transcript structure from UCSC…

Applied criteria · 1 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

PS

PM

PP

Benign evidence

BA

BS

BP

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

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