Classification rationale

PM2 BP7BP4 Likely Benign

PMS2 c.321G>A

The PMS2 c.321G>A (p.Arg107=) variant has been reported in ClinVar predominantly as likely benign or benign, with a minority submission as uncertain significance.¹ This variant is present at very low frequency in population databases, including gnomAD v4.1 at 11/1598118 alleles (AF 0.0000068831; grpmax FAF 0.00000429) and gnomAD v2.1 at 5/236556 alleles (AF 0.0000211366), which is below the PMS2 PM2_Supporting threshold of 0.00002 in gnomAD v4 and far below the BS1 and BA1 thresholds.² In silico evidence supports a benign interpretation because this synonymous variant has no predicted splice effect by SpliceAI, with a maximum delta score of 0.00, supporting BP4 and consistent with BP7.³

PM2 + BP7 + BP4 → Likely Benign

1 clinvar ↗

2 gnomad_v4 ↗gnomad_v2 ↗cspec ↗

3 spliceai ↗cspec ↗

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

PMS2 NM_000535.7

Fetching transcript structure from UCSC…

Applied criteria · 3 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= 6.8831e-06; MAF= 0.00069%, 11/1598118 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 1.66789e-05; MAF= 0.00167%, 1/59956 alleles, homozygotes = 0); grpmax FAF= 4.29e-06.

v2.1

This variant is present in gnomAD v2.1 (AF= 2.11366e-05; MAF= 0.00211%, 5/236556 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 3.66381e-05; MAF= 0.00366%, 4/109176 alleles, homozygotes = 0); grpmax FAF= 1.156e-05.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.00069% · 11 / 1,598,118
0 hom · FAF 0.00043%

Admixed American 1 / 59,956	0.0017%
European (non-Finnish) 10 / 1,178,204	0.00085%

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

gnomAD v2.1

0.0021% · 5 / 236,556
0 hom · FAF 0.0012%

European (non-Finnish) 4 / 109,176	0.0037%
Admixed American 1 / 34,424	0.0029%

+ 6 not observed (African/African 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 (6 clinical laboratories) and as Uncertain significance (1 clinical laboratory) and as Likely Benign (1 clinical laboratory) and as Benign (1 clinical laboratory).

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB oncogenicity for this specific variant: Unknown Oncogenic Effect (variant has not been individually curated).

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots