Back
LYFE SCIENCES
Project: HERA
NM_024675.3:c.514_517del
p.Ser172GlyfsTer4  ·  PALB2
Starting
Initialising…
0%
Legacy Engine
Ready
View Legacy →
Classification rationale
1

The PALB2 NM_024675.3:c.514_517del (NP_078951.2:p.(Ser172GlyfsTer4); p.(S172Gfs*4)) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar as pathogenic, including expert panel review.

clinvar ↗
2

This variant is absent from gnomAD v4.1 and gnomAD v2.1, placing its observed population frequency below the PALB2 PM2_Supporting threshold of 0.000333% and well below the BS1 and BA1 thresholds.

gnomad_v4 ↗ gnomad_v2 ↗ cspec ↗
3

This deletion causes an early frameshift with a premature stop codon, and the PALB2 disease-specific framework supports loss-of-function interpretation for this null variant with PVS1_VeryStrong and PM5_Supporting for a truncating variant upstream of p.Tyr1183.

cspec ↗
4

SpliceAI predicts no significant splice impact for this variant (max delta score 0.00), so PP3 is not met and the interpretation is driven by the truncating effect rather than an added predicted splice defect.

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
—
—
Rationale
Select a criterion to inspect its explanation.
Evidence used
  • —
Gaps remaining
  • —
Rule
—
Publications
—
Research and evidence
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Pathogenic (5 clinical laboratories) and as Pathogenic by ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen (expert panel). (ClinVarID = 461007)
ClinVar ↗
Functional evidence
03
Functional
OncoKB: Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
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.
ResidueS172
Hotspots ↗