LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-05-09
Case ID: NM_024675.3_c.7G_T_20260509_211126
Framework: ACMG/AMP 2015
Variant classification summary

NM_024675.3:c.7G>T

PALB2  · NP_078951.2:p.(Glu3Ter)  · NM_024675.3
GRCh37: chr16:23652472 C>A  ·  GRCh38: chr16:23641151 C>A
Gene: PALB2 Transcript: NM_024675.3
Final call
Pathogenic
PVS1 very strong PM2 supporting PM5 supporting PP5 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
PALB2
Transcript
NM_024675.3
Protein
NP_078951.2:p.(Glu3Ter)
gnomAD AF
ClinVar
OncoKB
Likely Oncogenic
Classification rationale
Interpretation summary
Generated evidence synthesis
1
The PALB2 c.7G>T (p.Glu3Ter, p.E3*) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar as pathogenic, including review by the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer expert panel.
2
This variant is absent from gnomAD v2.1 and gnomAD v4.1, placing it below the PALB2 PM2_Supporting population threshold of 0.000333%.
3
This variant introduces a premature stop codon at amino acid 3, and the active PALB2 expert specification supports loss of function as an established disease mechanism, consistent with application of PVS1 and the PALB2 truncation-based PM5 rule.
4
SpliceAI predicts a limited splice effect with a maximum delta score of 0.15, which is below the PALB2 PP3 threshold of 0.2 and above the BP4 threshold of 0.1, so computational splice evidence is indeterminate; a BayesDel score of 0.63 is available but is not the governing PP3/BP4 rule in this gene-specific framework.
Final determination: Rule4 in the Richards et.al., 2015 - Combining rules v1.2.0 criteria-combination framework is satisfied by the adjudicated criteria, so the variant is classified as Pathogenic.
Criteria assessment
ACMG/AMP criteria review
Criteria shown when status is available
All criteria require review: For research and educational purposes only.
Criterion Status Rationale Evidence used
PVS1 Met This nonsense variant, NM_024675.3:c.7G>T (p.Glu3Ter, p.E3*), introduces a premature stop codon at amino acid 3 in PALB2. The PALB2 expert specification includes gene-specific PVS1 guidance, and available gene-level context supports loss of function as an established disease mechanism, so this early truncating variant meets PVS1 at very strong strength.
cspec pvs1_gene_context pvs1_variant_assessment
PS1 Not met Available evidence does not identify a PALB2 PS1 splicing-table match or another variant with the same proven RNA effect needed to apply PS1 for this variant.
cspec spliceai
PS2 N/A PS2 is not applied in the PALB2 expert specification for this disease context.
cspec
PS3 N/A PS3 is not applied in the PALB2 expert specification for this disease context, so published literature was not used to assign a PS3 strength here.
cspec oncokb
PS4 Not assessed This variant has been reported in ClinVar, but no case-control study or exact-variant prevalence data were identified showing a significant enrichment in affected individuals that meets the PALB2 PS4 threshold.
cspec clinvar PMID:25099575
PM1 N/A PM1 is not applied for PALB2 in this expert specification.
cspec hotspots
PM2 Met This variant is absent from gnomAD v4.1 and gnomAD v2.1. Its observed population frequency is therefore below the PALB2 PM2_Supporting threshold of 1 in 300,000 (0.000333%), supporting PM2 at supporting strength.
cspec gnomad_v4 gnomad_v2
PM3 Not assessed No confirmed in trans observations with another pathogenic PALB2 variant in individuals with Fanconi anemia were identified, so PM3 cannot be assigned from the available evidence.
cspec PMID:17200671
PM4 N/A PM4 is not applicable because this is a nonsense variant, and the PALB2 expert specification restricts PM4 to stop-loss variants rather than truncating variants such as this one.
cspec
PM5 Met The PALB2 expert specification repurposes PM5 for truncating variants with premature termination codons upstream of p.Tyr1183. This variant creates p.Glu3Ter (p.E3*), which is far upstream of p.Tyr1183, so PM5 is met at supporting strength under the gene-specific truncation rule.
cspec pm5_candidates
PM6 N/A PM6 is not applied in the PALB2 expert specification for this disease context.
cspec
PP1 Not assessed No quantitative segregation data, LOD score, or Bayes factor were identified for this variant, so PP1 cannot be assigned from the available evidence.
cspec clinvar
PP2 N/A PP2 is not applied for PALB2 in this expert specification.
cspec
PP3 Not met For PALB2, PP3 is used for predicted splice impact when SpliceAI is at least 0.2. This variant has a SpliceAI max delta score of 0.15, which is below the 0.2 threshold, so PP3 is not met. A BayesDel score of 0.63 is available, but the PALB2 expert specification uses the splice-prediction rule for PP3/BP4 in this context.
cspec spliceai bayesdel
PP4 N/A PP4 is not applied for PALB2-related autosomal dominant cancer predisposition in this expert specification.
cspec
PP5 Met Expert panel ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen classified as Pathogenic.
cspec clinvar
BA1 Not met This variant is absent from gnomAD v4.1 and therefore is well below the PALB2 BA1 threshold of greater than 0.1%. BA1 is not met.
cspec gnomad_v4
BS1 Not met This variant is absent from gnomAD v4.1 and therefore is below the PALB2 BS1 threshold of greater than 0.01%. BS1 is not met.
cspec gnomad_v4
BS2 Not assessed No qualifying observations in unaffected individuals with the point-based evidence required by the PALB2 Fanconi anemia BS2 framework were identified, so BS2 cannot be assigned.
cspec
BS3 N/A BS3 is not applied for PALB2 in this expert specification.
cspec oncokb
BS4 Not assessed No quantitative non-segregation evidence, LOD score, or Bayes factor showing lack of segregation with disease was identified for this variant, so BS4 cannot be assigned.
cspec clinvar
BP1 N/A BP1 applies to missense variants in PALB2. This variant is a nonsense change, so BP1 is not applicable.
cspec
BP2 N/A BP2 is not applied for PALB2 in this expert specification.
cspec
BP3 N/A BP3 is not applied for PALB2 in this expert specification.
cspec
BP4 Not met For PALB2, BP4 for splice prediction requires SpliceAI of 0.1 or less. This variant has a SpliceAI max delta score of 0.15, which is above the benign threshold, so BP4 is not met. A BayesDel score of 0.63 is available, but the PALB2 expert specification uses the splice-prediction rule for PP3/BP4 in this context.
cspec spliceai bayesdel
BP5 N/A BP5 is not applied for PALB2 in this expert specification.
cspec
BP6 N/A BP6 is not applied in the PALB2 expert specification.
cspec clinvar
BP7 N/A BP7 applies to synonymous and certain deep intronic variants. This variant is a nonsense substitution in the coding sequence, so BP7 is not applicable.
cspec
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