LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-04-17
Case ID: NM_024675.4_c.2329G_A_20260417_171955
Framework: ACMG/AMP 2015
Variant classification summary

NM_024675.4:c.2329G>A

PALB2  · NP_078951.2:p.(Asp777Asn)  · NM_024675.4
GRCh37: chr16:23641146 C>T  ·  GRCh38: chr16:23629825 C>T
Gene: PALB2 Transcript: NM_024675.4
Final call
VUS
BP1_Supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
PALB2
Transcript
NM_024675.4
Protein
NP_078951.2:p.(Asp777Asn)
gnomAD AF
ClinVar
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
The PALB2 c.2329G>A (p.Asp777Asn; p.D777N) variant has been observed in somatic cancers in COSMIC 3 times (COSV55162903) and has not been reported in ClinVar.
2
This variant is present in gnomAD v4.1 at 35/1,614,078 alleles (AF 0.00217%), with highest observed frequency in East Asian individuals at 4/44,886 alleles (AF 0.00891%) and grpmax FAF 0.00298%, which is above the PALB2 PM2_Supporting threshold of 0.000333% and below the BS1 threshold of 0.01%.
3
SpliceAI predicts no significant splice impact for this variant (max delta score 0.01), and REVEL is low at 0.038; however, PALB2 missense specifications do not use PP3 or BP4 for missense variants.
Final determination: BP1 supporting alone does not meet the PALB2 final-classification threshold for likely benign or benign classification; therefore this variant is classified as a variant of uncertain significance.
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 N/A This is a missense variant, and PALB2 PVS1 is reserved for predicted loss-of-function variants using the PALB2 PVS1 decision tree.
cspec
PS1 N/A Available evidence does not indicate that this missense variant matches a PALB2 splicing-table PS1 scenario, and the PALB2 PS1 specification is restricted to the PALB2 PS1 splicing table.
cspec spliceai
PS2 N/A PS2 is not used under the PALB2 specification.
cspec
PS3 N/A PS3 is not used under the PALB2 specification.
cspec
PS4 Not assessed This variant has been observed in COSMIC 3 times, but no germline case-control study showing significant enrichment in affected individuals was identified, so available evidence does not support PS4 assessment.
cspec cosmic clinvar literature_pass
PM1 N/A PM1 is not used under the PALB2 specification.
cspec
PM2 Not met This variant is present in gnomAD v4.1 at 35/1,614,078 alleles (AF 0.00217%), with grpmax FAF 0.00298%. The observed frequency is above the PALB2 PM2_Supporting threshold of 0.000333%, so PM2 is not met.
cspec gnomad_v4
PM3 Not assessed No data were identified showing this variant in trans with a pathogenic PALB2 variant in Fanconi anemia probands, so PM3 cannot be assessed.
cspec literature_pass
PM4 N/A PM4 is not used under the PALB2 specification.
cspec
PM5 N/A This is a missense variant, whereas PALB2 PM5_Supporting is restricted to truncating or qualifying splice variants that create premature termination codons upstream of p.Tyr1183.
cspec
PM6 N/A PM6 is not used under the PALB2 specification.
cspec
PP1 Not assessed No segregation data were identified for this variant, so PP1 cannot be assessed.
cspec literature_pass
PP2 N/A PP2 is not used under the PALB2 specification.
cspec
PP3 N/A SpliceAI predicts no significant splice effect with a max delta score of 0.01, and PALB2 PP3 is not used for missense variants. Therefore PP3 is not applicable.
cspec spliceai
PP4 N/A PP4 is not used under the PALB2 specification.
cspec
PP5 N/A PP5 is not used under the PALB2 specification.
cspec
BA1 Not met This variant is present in gnomAD v4.1 with grpmax FAF 0.00298%, which is below the PALB2 BA1 threshold of 0.1%, so BA1 is not met.
cspec gnomad_v4
BS1 Not met This variant is present in gnomAD v4.1 with grpmax FAF 0.00298%, which is below the PALB2 BS1 threshold of 0.01%, so BS1 is not met.
cspec gnomad_v4
BS2 Not assessed No data were identified showing this variant in the number of unaffected individuals required by the PALB2 Fanconi anemia BS2 point system, so BS2 cannot be assessed.
cspec literature_pass
BS3 N/A BS3 is not used under the PALB2 specification.
cspec
BS4 Not assessed No nonsegregation data were identified for this variant, so BS4 cannot be assessed.
cspec literature_pass
BP1 Met This is a missense variant, and the PALB2 specification applies BP1_Supporting to all missense variants.
cspec case_summary
BP2 N/A BP2 is not used under the PALB2 specification.
cspec
BP3 N/A BP3 is not used under the PALB2 specification.
cspec
BP4 N/A SpliceAI predicts no significant splice effect with a max delta score of 0.01, but PALB2 BP4 is not used for missense variants. Therefore BP4 is not applicable.
cspec spliceai
BP5 N/A BP5 is not used under the PALB2 specification.
cspec
BP6 N/A BP6 is not used under the PALB2 specification.
cspec
BP7 N/A This is a missense variant rather than a synonymous or qualifying deep intronic variant, so BP7 is not applicable.
cspec case_summary
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