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
Final classification
Pathogenic
PVS1PM2PP5PM5
PALB2
c.2524_2535delinsTCAGA
p.Ala842SerfsTer7
This variant
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
LYFE Sciences is an AI system, and it can make mistakes. Criteria
may be applied incorrectly, sources may be misread, and a confident-looking
classification can still be wrong. Double-check every criterion and
its underlying evidence before relying on any call.
Gene diagram
· NM_024675.3 · variants mapped to exon structure
PALB2
NM_024675.3
Fetching transcript structure from UCSC…
Applied criteria · 4 applied · 9 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 4
Strength
Supporting
Moderate
Strong
Very strong
PVS1
very strong
review
Pathogenic
This frameshift variant is predicted to cause p.(Ala842SerfsTer7) / p.(A842Sfs*7), introducing a premature termination codon in exon 6 of 13 and well upstream of the last exon, which is consistent with nonsense-mediated decay of a PALB2 transcript in a gene where loss of function is an established disease mechanism. Available evidence supports applying PVS1 at very strong strength.
PALB2 CSPEC marks PVS1 as applicable and uses a PALB2 PVS1 decision tree.Gene-level PVS1 context states PALB2 loss of function is an established disease mechanism.The variant is a frameshift with predicted protein consequence p.(Ala842SerfsTer7) / p.(A842Sfs*7)
PM2
supporting
Pathogenic
This variant is absent from gnomAD v4.1 and gnomAD v2.1. Its frequency is therefore below the PALB2 PM2_Supporting threshold of 1/300,000 (0.000333%), so PM2_Supporting is met.
gnomAD v4.1: absent.gnomAD v2.1: absent.PALB2 PM2 is used at supporting strength only.
PM5
supporting
Pathogenic
This variant is a truncating frameshift predicted to introduce p.(Ala842SerfsTer7), which is upstream of the PALB2 VCEP truncation cutoff at p.Tyr1183*. This supports applying PM5_Supporting under the PALB2 specification.
Predicted protein consequence: p.(Ala842SerfsTer7) / p.(A842Sfs*7).PALB2 PM5_Supporting applies to frameshifting or truncating variants with premature termination codons upstream of p.Tyr1183*.
PP5
supporting
Pathogenic
Expert panel ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen classified as Pathogenic.
PALB2 CSPEC marks PP5 as not applicable for this VCEP.ClinVar expert-panel classification was reviewed but not used as PP5 evidence.ClinVar expert panel classification
Assessed · not applied
· 3 not met · 6 not assessed
Pathogenic
PS1
No evidence was identified that this variant matches a PALB2 PS1 splicing-table entry, so PS1 was not assessed.
PS4
No case-control study was identified showing this exact variant is significantly enriched in affected individuals, so the PALB2 PS4 threshold is not met.
PM3
No evidence was identified that this variant was observed in trans with another pathogenic PALB2 variant in a proband with Fanconi anemia, so PM3 cannot be assessed.
PP1
No segregation data were identified for this variant, so PP1 cannot be assessed.
Benign
BA1
This variant is absent from gnomAD v4.1, which is below the PALB2 BA1 threshold of greater than 0.1%, so BA1 is not met.
BS1
This variant is absent from gnomAD v4.1, which is below the PALB2 BS1 threshold of greater than 0.01%, so BS1 is not met.
BS2
No qualifying observations of this variant in healthy individuals under the PALB2 BS2 framework were identified, so BS2 cannot be assessed.
BS4
No non-segregation data were identified for this variant, so BS4 cannot be assessed.
BP4
SpliceAI predicts no significant splice impact with a maximum delta score of 0.10, which is at the PALB2 BP4 splice threshold.
N/A · 15
PS2 · PS3 · PM1 · PM4 · PM6 · PP2 · PP3 · PP4 · BS3 · BP1 · BP2 · BP3 · BP5 · BP6 · BP7
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.
A practice guideline from the American College of Medical Genetics and Genomics
Found
Structured finding pending for this record — see source link.
Applied to
→PP5
supporting
Sources & reference links