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LYFE SCIENCES
Project: HERA
NM_024675.3:c.3089C>T
p.Thr1030Ile  ·  PALB2
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Classification rationale
1

The PALB2 c.3089C>T (p.Thr1030Ile) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar, where the current overall interpretation is uncertain significance, including an expert panel review.

clinvar ↗
2

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

gnomad_v2 ↗ gnomad_v4 ↗ cspec ↗
3

In published functional studies, p.(Thr1030Ile) showed abnormal behavior in PALB2 DNA-repair assays, including protein instability, altered interactions within the BRCA2/RAD51C repair complex, marked homologous recombination defects, impaired recruitment to DNA damage sites, cytoplasmic accumulation, and increased PARP inhibitor sensitivity, consistent with a damaging effect.

PMID:24141787 ↗ PMID:31586400 ↗
4

SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.01, which is below the PALB2 PP3 splicing threshold of 0.2; REVEL is 0.434 and BayesDel is -0.0862002, but the PALB2 expert specification does not use missense in silico scores for PP3/BP4 adjudication.

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
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Uncertain significance (4 clinical laboratories) and as Uncertain Significance by ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen (expert panel). (ClinVarID = 232977)
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 = 0.01). REVEL score = 0.434. BayesDel score = -0.0862002.
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.
ResidueT1030
Hotspots ↗