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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 NM_000535.7:c.241G>A (p.Glu81Lys, p.E81K) variant has been observed once in somatic cancers in COSMIC and has been reported in ClinVar mostly as uncertain significance, with one benign submitter and no expert-panel classification.

clinvar ↗
2

This variant is present in gnomAD v4.1 at AF 0.00003262 (52/1593986 alleles) with grpmax FAF 0.00009008, which is above the PMS2 PM2_Supporting rarity threshold of <0.00002 and below the BS1 threshold of >=0.00028.

gnomad_v4 ↗ gnomad_v2 ↗ cspec ↗
3

Computational evidence supports BP4 because the PMS2 HCI prior probability is 0.0446, below the <0.11 benign threshold; SpliceAI predicts no significant splice impact (max delta 0.00), while REVEL is 0.516 and BayesDel is 0.0236541.

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 v2 ↗ gnomAD v4 ↗
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 ↗