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

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

PMS2 NM_000535.7

Fetching transcript structure from UCSC…

Applied criteria · 2 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 · 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