LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-06-22
Case ID: NM_024675.4_c.2580G_T_20260622_162617
Framework: ACMG/AMP 2015
Variant classification summary

NM_024675.4:c.2580G>T

PALB2  · NP_078951.2:p.(Glu860Asp)  · NM_024675.4
GRCh37: chr16:23640531 C>A  ·  GRCh38: chr16:23629210 C>A
Gene: PALB2 Transcript: NM_024675.4
Final call
PM2 supporting BP1 supporting benign
All criteria require review: For research and educational purposes only.
Variant details
Gene
PALB2
Transcript
NM_024675.4
Protein
NP_078951.2:p.(Glu860Asp)
gnomAD AF
ClinVar
Uncertain significance
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
NM_024675.4:c.2580G>T (p.Glu860Asp) is a missense variant in PALB2, a gene where loss of function is an established mechanism of disease but missense pathogenicity is not yet confirmed.
2
The variant is absent from gnomAD v2.1 and v4.1, meeting the VCEP PM2_Supporting criterion (frequency ≤ 0.000333%).
3
Per VCEP PALB2 specification, BP1_Supporting is applied to all missense variants given the very low likelihood that missense variants in PALB2 are pathogenic.
4
Multiple VCEP criteria are not applicable to missense variants in PALB2: PVS1, PS1, PM1, PM5, PP2, PP3, BP4. Additional criteria (PS3, BS3, PS2, PM6, PP4, PP5, BP2, BP5, BP6) are not applicable per VCEP specification.
5
SpliceAI predicts no splice impact (max delta 0.01). REVEL score (0.021) and BayesDel score (-0.521846) are consistent with a benign computational prediction for the missense change, though not formally applied as criteria per VCEP rules.
6
ClinVar reports this variant as Uncertain significance (4 clinical laboratories) and Likely benign (1 clinical laboratory). No expert panel classification is available.
7
With PM2_Supporting (1 pathogenic supporting point) and BP1_Supporting (1 benign supporting point), the variant falls into the Uncertain Significance category per ACMG/AMP 2015 combination rules (Rule 31: conflicting supporting evidence).
Final determination: Rule31 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 Uncertain Significance - Conflicting Evidence.
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 Missense variant (p.Glu860Asp); does not meet PVS1 null-variant criteria (nonsense, frameshift, canonical splice ±1,2). PALB2 PVS1 Decision Tree applies to null variants, not missense substitutions.
pvs1_variant_assessment cspec
PS1 N/A VCEP PALB2 specification: PS1 is not used for missense variants. Missense changes are not yet confirmed as a mechanism of disease for PALB2.
cspec
PS2 N/A VCEP PALB2 specification: PS2 is not applicable. Informative de novo occurrences have not yet been observed for autosomal dominant PALB2-related disease.
cspec
PS3 N/A VCEP PALB2 specification: PS3 is not applicable for protein-level functional studies. Color Health submission notes 'functional studies have not been performed for this variant.'
cspec clinvar
PS4 Not assessed VCEP requires case-control studies with p≤0.05 AND (OR≥3 OR lower 95% CI ≥1.5). No case-control study meeting this threshold has been identified for this variant. ClinVar reports 5 clinical laboratory submissions (4 VUS, 1 likely benign) but no case-control data.
cspec clinvar
PS5 Not assessed No pathogenic missense variant has been established at codon Glu860 in PALB2. Insufficient evidence to apply PS5 (same amino acid change as established pathogenic variant).
pm5_candidates
PM1 N/A VCEP PALB2 specification: PM1 is not applicable. Missense pathogenic variation in PALB2 is not yet confirmed as a mechanism of disease.
cspec
PM2 Met Variant is absent from gnomAD v2.1 (exomes) and gnomAD v4.1 (exomes). Meets VCEP PM2_Supporting threshold (frequency ≤ 0.000333% in gnomAD v4).
gnomad_v2 gnomad_v4
PM5 N/A VCEP PALB2 specification: PM5 is restricted to frameshifting or truncating variants with premature termination codons upstream of p.Tyr1183, or splice variants with NMD-prone PTCs. Not applicable to missense variants.
cspec
PM6 N/A VCEP PALB2 specification: PM6 is not applicable. Informative de novo occurrences have not yet been observed for PALB2-related disease.
cspec
PP1 Not assessed No co-segregation data available for this variant. VCEP requires quantitative co-segregation analysis (LOD scores or Bayes Factors for AD condition) or affected relative counts for AR condition.
cspec
PP2 N/A VCEP PALB2 specification: PP2 is not applicable. Missense is not yet confirmed or refuted as a mechanism of disease for PALB2.
cspec
PP3 N/A VCEP PALB2 specification: PP3 is not used for missense variants. PP3 applies only to splicing predictions (SpliceAI ≥0.2). SpliceAI max delta score is 0.01, which does not meet the splicing threshold. REVEL score 0.021 and BayesDel score -0.521846 are consistent with a benign computational prediction but are not applied under VCEP rules.
cspec spliceai revel bayesdel
PP4 N/A VCEP PALB2 specification: PP4 is not applicable. Breast cancer has multiple genetic etiologies and no features readily distinguish hereditary from sporadic causes.
cspec
PP5 N/A VCEP PALB2 specification: PP5 is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
cspec
BA1 Not met Variant is absent from gnomAD v4.1. Does not meet the VCEP BA1 threshold (Grpmax Filtering AF >0.1% in gnomAD v4).
gnomad_v4 cspec
BS1 Not met Variant is absent from gnomAD v4.1. Does not meet the VCEP BS1 threshold (Grpmax Filtering AF >0.01% in gnomAD v4).
gnomad_v4 cspec
BS2 Not assessed VCEP BS2 requires Fanconi Anemia proband points from BS2 tables. No Fanconi Anemia proband data available for this variant.
cspec
BS3 N/A VCEP PALB2 specification: BS3 is not applicable for protein-level functional studies. No variant-specific benign functional evidence identified.
cspec
BS4 Not assessed VCEP BS4 requires quantitative co-segregation analysis (LOD scores or Bayes Factors). No segregation data available for this variant.
cspec
BP1 Met VCEP PALB2 specification: BP1 applies to all missense variants at supporting benign strength. PALB2 has a low rate of missense variants that are non-functional in relevant assays, and true missense pathogenic variants are thought to be exceedingly rare.
cspec
BP2 N/A VCEP PALB2 specification: BP2 is not applicable. Uses ATM PM3/BP2 table; not relevant for PALB2.
cspec
BP3 N/A Skipped per case directive; substitution variant, not an in-frame deletion/insertion.
BP4 N/A VCEP PALB2 specification: BP4 is not used for missense variants. Published predictors have yet to achieve reliable functional outcome prediction for PALB2 missense variants. SpliceAI max delta 0.01 is ≤0.1 but BP4 is explicitly not applicable to missense variants.
cspec spliceai
BP5 N/A VCEP PALB2 specification: BP5 is not applicable. Cases with multiple pathogenic variants have been observed with no noticeable difference in phenotype; PALB2 has moderate penetrance.
cspec
BP6 N/A VCEP PALB2 specification: BP6 is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
cspec
BP7 N/A BP7 is restricted to synonymous and deep intronic variants beyond +7 (donor) and -21 (acceptor). NM_024675.4:c.2580G>T is a missense variant in exon 6; BP7 does not apply.
cspec
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