The PALB2 c.2524_2535delinsTCAGA (p.(Ala842SerfsTer7)) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar as pathogenic, including an expert-panel pathogenic classification.1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, placing it below the PALB2 PM2_Supporting population threshold of 0.000333%.2 The predicted consequence is a frameshift with premature termination, p.(Ala842SerfsTer7), in a gene where loss of function is an established disease mechanism, supporting truncating-variant evidence under the PALB2 specification.3 SpliceAI predicts no significant splice effect for this variant, with a maximum delta score of 0.10, supporting interpretation of the variant as a truncating allele rather than a splice-altering event.4
PALB2
Final classification
Pathogenic
PALB2 c.2524_2535delinsTCAGA · p.Ala842SerfsTer7
PALB2
The PALB2 c.2524_2535delinsTCAGA (p.(Ala842SerfsTer7)) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar as pathogenic, including an expert-panel pathogenic classification.
Richards et.al., 2015 - Combining rules v1.2.0 criteria-combination framework: matched Rule4 (1 Pathogenic.Very Strong + Pathogenic.Supporting >=2) with applied criteria: PVS1 very strong, PM2 supporting, PP5 supporting, PM5 supporting; maps to Pathogenic.
Classification rationale
PVS1PM2PP5PM5
Pathogenic
PALB2 c.2524_2535delinsTCAGA
PVS1 + PM2 + PP5 + PM5
→
Pathogenic
3
cspec ↗pvs1_gene_contextpvs1_variant_assessment
Gene diagram
· NM_024675.3 · variants mapped to exon structure
PALB2
NM_024675.3
Fetching transcript structure from UCSC…
Applied criteria · 4 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Pathogenic (1 clinical laboratory) and as Pathogenic by ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen (expert panel).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.10).
Functional
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.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Literature · how each cited paper was used
1papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why.
PMID PMID:25394175
Found
Structured finding pending for this record — see source link.
Applied to
→PP5 supports · met
Sources & reference links