Classification rationale

BP7BP4 Likely Benign

PMS2 c.23+32dup

The PMS2 NM_000535.7:c.23+32dup (NP_000526.2:p.?) variant has been reported in ClinVar as likely benign by one clinical laboratory.¹ In gnomAD, this variant has a v4.1 total allele frequency of 5.0248e-05 (81/1612004 alleles) and a grpmax filtering allele frequency of 5.301e-05, which is above the PMS2 PM2 threshold of 0.00002 but below the BS1 threshold of 0.00028.² This intronic duplication is located at c.23+32, beyond the PMS2 BP7 boundary of +7, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.02, supporting BP7 and BP4 while arguing against PP3 and PVS1.³

BP7 + BP4 → Likely Benign

1 clinvar ↗

2 gnomad_v4 ↗cspec ↗

3 cspec ↗spliceai ↗pvs1_variant_assessment

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 · 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 · 2

Strength Supporting Moderate Strong Very strong

BP4 supporting review Benign

SpliceAI predicts no significant splice impact for this intronic duplication, with a maximum delta score of 0.02, which is below the PMS2 VCEP BP4 threshold of 0.1.

SpliceAI maximum delta score = 0.02.PMS2 VCEP BP4 for intronic variants requires SpliceAI delta score <= 0.1.

cspec ↗spliceai ↗

BP7 supporting review Benign

This intronic duplication is located at c.23+32, which is beyond the +7 intronic threshold specified for BP7, meeting the PMS2 VCEP location requirement for a benign supporting code.

Variant nomenclature places the change at intronic position +32.PMS2 VCEP BP7 applies to intronic variants at or beyond +7.

cspec ↗

Assessed · not applied · 5 not met · 11 not assessed

Pathogenic

PVS1 This deep intronic duplication does not fall within the PMS2 VCEP default PVS1 categories for nonsense, frameshift, canonical splice, or qualifying large rearrangement variants, and no patient RNA evidence was identified to show that the variant causes a loss-of-function splicing abnormality.

PS1 No evidence was identified that this variant affects the same non-canonical splice nucleotide as a previously established pathogenic or likely pathogenic PMS2 splice variant with similar or worse predicted splicing impact.

PS2 No de novo data with the required tumor context or parental confirmation were identified, so this criterion cannot be assessed from the available evidence.

PS3 No calibrated functional assay or constitutional RNA study demonstrating a damaging effect was identified for this variant.

PM2 The gnomAD v4.1 total allele frequency is 5.0248e-05 (81/1612004 alleles; 0.00502%), which is above the PMS2 VCEP PM2 threshold of 0.00002 (1 in 50,000 alleles), so PM2 is not met.

PM3 No observations were identified to score this variant in trans with another pathogenic PMS2 variant for the PMS2 VCEP PM3 point system.

PM5 This is not a missense variant, and no evidence was identified to support applying a same-residue missense rule.

PP1 No segregation data were identified, so co-segregation support cannot be assessed.

PP3 SpliceAI predicts a maximum delta score of 0.02, which is below the PMS2 VCEP PP3 threshold of 0.2 for a predicted splice defect, so PP3 is not met.

PP4 No MSI-high tumor findings or mismatch repair protein loss data consistent with PMS2 were identified, so phenotype-based support is not established.

Benign

BA1 The gnomAD v4.1 grpmax filtering allele frequency is 5.301e-05 (0.005301%), which is below the PMS2 VCEP BA1 threshold of 0.0028 (0.28%), so BA1 is not met.

BS1 The gnomAD v4.1 grpmax filtering allele frequency is 5.301e-05 (0.005301%), which is below the PMS2 VCEP BS1 range threshold of 0.00028 (0.028%), so BS1 is not met.

BS2 No evidence was identified that this variant co-occurs in trans with a known pathogenic PMS2 variant in a person meeting the PMS2 VCEP conditions for BS2.

BS3 No functional or RNA evidence demonstrating no damaging effect was identified for this variant.

BS4 No non-segregation data were identified, so BS4 cannot be assessed.

BP5 No tumor profile data were identified to show mismatch repair findings inconsistent with PMS2-associated disease, so BP5 cannot be assessed.

N/A · 10 PS4 · PM1 · PM4 · PM6 · PP2 · PP5 · BP1 · BP2 · BP3 · BP6

Research & evidence

Population frequency · supports benign

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 5.0248e-05; MAF= 0.00502%, 81/1612004 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 6.52867e-05; MAF= 0.00653%, 77/1179414 alleles, homozygotes = 0); grpmax FAF= 5.301e-05.

v2.1

This variant is present in gnomAD v2.1 (AF= 7.99226e-06; MAF= 0.00080%, 2/250242 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.77292e-05; MAF= 0.00177%, 2/112808 alleles, homozygotes = 0); grpmax FAF= 2.94e-06.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.005% · 81 / 1,612,004
0 hom · FAF 0.0053%

European (non-Finnish) 77 / 1,179,414	0.0065%
Remaining individuals 2 / 62,338	0.0032%
African/African American 2 / 74,870	0.0027%

+ 7 not observed (Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish)

gnomAD v2.1

0.0008% · 2 / 250,242
0 hom · FAF 0.00029%

European (non-Finnish)

2 / 112,808

0.0018%

+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Likely benign (1 clinical laboratory).

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).

SpliceAI ↗

Functional No data

No calibrated functional assay or RNA evidence was identified for this variant.

OncoKB ↗

COSMIC

Somatic evidence

COSMIC

This variant has previously been reported in somatic cancers (COSMIC; COSV56151367, n = 1 times).

Hotspots

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

COSMIC ↗

Sources & reference links

7Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

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