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LYFE SCIENCES
Project: HERA
NM_024675.3:c.682C>T
p.Gln228Ter  ·  PALB2
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Classification rationale
1

The PALB2 c.682C>T (p.Gln228Ter; p.Q228*) variant has been reported in ClinVar as pathogenic, including review by the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel.

clinvar ↗
2

This variant is absent from gnomAD v2.1 and is present only once in gnomAD v4.1 at an overall allele frequency of 0.00006% (1/1,614,016 alleles), which is below the PALB2 PM2_Supporting threshold of 0.000333%.

gnomad_v2 ↗ gnomad_v4 ↗ cspec ↗
3

This variant introduces a premature stop codon early in PALB2, and published PALB2 studies together with the PALB2 specification support loss of function as an established disease mechanism for hereditary cancer predisposition.

cspec ↗ PMID:17200671 ↗ PMID:25099575 ↗ PMID:28779002 ↗
4

SpliceAI predicts no significant splice impact for this variant (max delta score 0.01), which does not support PP3 and is consistent with the primary consequence being protein truncation rather than altered splicing.

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 v2.1Absent from gnomAD v2.1.
gnomAD v4.1This variant is present in gnomAD v4.1 (AF= 6.19573e-07; MAF= 0.00006%, 1/1614016 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47448e-07; MAF= 0.00008%, 1/1180014 alleles, homozygotes = 0).
gnomAD v2 ↗ gnomAD v4 ↗
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).
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). BayesDel score = 0.63.
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; COSV55168872, n = 1 times).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueQ228
Hotspots ↗