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LYFE SCIENCES
Project: HERA
NM_000535.7:c.241G>A
p.Glu81Lys  ·  PMS2
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Classification rationale
1

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.

clinvar ↗
2

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.

gnomad_v4 ↗ gnomad_v2 ↗ cspec ↗
3

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.

spliceai ↗ cspec ↗
Applied criteria
Met
Not met
Not assessed
N/A
Very strong
Strong
Moderate
Supporting
Pathogenic evidence
PVS
PVS1
PS
PS1
PS2
PS3
PS4
PM
PM1
PM2
PM3
PM4
PM5
PM6
PP
PP1
PP2
PP3
PP4
PP5
Benign evidence
BA
BA1
BS
BS1
BS2
BS3
BS4
BP
BP1
BP2
BP3
BP4
BP5
BP6
BP7
PVS1
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Rationale
Select a criterion to inspect its explanation.
Evidence used
  • —
Gaps remaining
  • —
Rule
—
Publications
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Research and evidence
gnomAD v2.1 evidence
v2.1
gnomAD v4.1 evidence
v4.1
01
Population
gnomAD v2.1This 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.
gnomAD v4.1This 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.
gnomAD CanadaThis 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).
gnomAD v2 ↗ gnomAD v4 ↗ gnomAD 🇨🇦 ↗
ClinVar evidence
02
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 ↗
Functional evidence
03
Functional
OncoKB: 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 ↗
In silico evidence
04
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 ↗
COSMIC evidence
05
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).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueE81
Hotspots ↗