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 ↗

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 · 3 applied · 13 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 · 3

Strength Supporting Moderate Strong Very strong

PM2 supporting Pathogenic

Population frequency supports PM2 at supporting strength. In gnomAD v4.1, the allele frequency is 0.0000068831 (11/1598118 alleles) and the grpmax filtering allele frequency is 0.00000429, both below the PMS2 PM2 threshold of 0.00002.

gnomAD v4 total AF = 6.8831e-06 (11/1598118)gnomAD v4 grpmax FAF = 4.29e-06PM2 threshold = <2e-05

gnomad_v4 ↗cspec ↗

BP4 supporting Benign

For this synonymous variant, SpliceAI predicts no splicing impact with a max delta score of 0.00, which is below the PMS2 BP4 threshold of 0.10 and supports BP4.

SpliceAI max delta score = 0.00BP4 threshold for synonymous/intronic variants: <=0.10

cspec ↗spliceai ↗

BP7 supporting Benign

This variant is a synonymous exonic substitution and is outside the PMS2 BP7 splice-region window; SpliceAI also predicts no significant splice impact, which is consistent with BP7 being met.

p.(Arg107=) synonymous variantSpliceAI max delta score = 0.00

cspec ↗spliceai ↗

Assessed · not applied · 4 not met · 9 not assessed

Pathogenic

PVS1 PVS1 is not met because this variant is a synonymous substitution rather than a null variant, and SpliceAI predicts no significant splice impact.

PS2 No confirmed de novo occurrence with the tumor features required by the PMS2 specification was identified, so PS2 cannot be assessed from the available evidence.

PS3 No calibrated functional assay result or RNA study showing a damaging effect for this specific variant was identified, so PS3 cannot be applied.

PM3 No evidence was identified that this variant occurs in trans with another pathogenic PMS2 variant in a context informative for constitutional mismatch repair deficiency scoring, so PM3 cannot be assessed.

PP1 No segregation data were identified, so the Bayes likelihood ratio required for PP1 could not be calculated.

PP3 Computational evidence does not support PP3.

PP4 No colorectal or endometrial tumor MSI results, tumor genome findings, or immunohistochemistry results consistent with PMS2 loss were identified, so PP4 cannot be applied.

Benign

BA1 Population frequency does not meet BA1.

BS1 Population frequency does not meet BS1.

BS2 No evidence was identified that this variant co-occurs in trans with a known pathogenic PMS2 variant in an individual meeting the specification requirements for age and absence of CMMRD features, so BS2 cannot be assessed.

BS3 No variant-specific functional or RNA assay result demonstrating normal function or no mRNA aberration was identified, so BS3 cannot be applied.

BS4 No non-segregation data were identified, so the Bayes likelihood ratio required for BS4 could not be calculated.

BP5 No tumor data were identified showing microsatellite-stable disease, retained mismatch repair protein expression, or protein loss inconsistent with PMS2, so BP5 cannot be assessed.

N/A · 12 PS1 · PS4 · PM1 · PM4 · PM5 · 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= 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

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