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LYFE SCIENCES
Project: HERA
NM_024675.3:c.2787_2788dup
p.Asn930IlefsTer6  ·  PALB2
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Classification rationale
1

The PALB2 c.2787_2788dup (p.Asn930IlefsTer6; p.N930Ifs*6) variant has been reported in ClinVar as pathogenic, including an expert panel submission.

clinvar ↗
2

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

gnomad_v4 ↗ gnomad_v2 ↗ cspec ↗
3

This frameshift duplication is predicted to create p.(Asn930IlefsTer6), introducing a premature termination codon consistent with loss of function in a gene where loss of function is an established disease mechanism, and it truncates the protein upstream of p.Tyr1183, supporting PVS1 and PM5_Supporting under the PALB2 specification.

cspec ↗
4

SpliceAI shows a maximum delta score of 0.20, which suggests possible splice impact, but this was not applied as a separate PP3 or BP4 pathogenic criterion for this frameshift variant under the PALB2 rule set.

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 (2 clinical laboratories) and as Pathogenic by ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen (expert panel).
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 possible splice impact for this variant (max delta score = 0.20).
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.
ResidueN930
Hotspots ↗