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LYFE SCIENCES
Project: HERA
NM_000535.7:c.321G>A
p.Arg107=  ·  PMS2
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Classification rationale
1

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.

clinvar ↗
2

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.

gnomad_v4 ↗ gnomad_v2 ↗ cspec ↗
3

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.

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= 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.
gnomAD v4.1This 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.
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
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 ↗
Functional evidence
03
Functional
OncoKB: Unknown Oncogenic Effect
OncoKB oncogenicity for this specific variant: Unknown Oncogenic Effect (variant has not been individually curated).
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueR107
Hotspots ↗