Variant classification summary

NM_024675.4:c.2970A>T

PALB2 · NP_078951.2:p.(Glu990Asp) · NM_024675.4

GRCh37: chr16:23634316 T>A · GRCh38: chr16:23622995 T>A

Gene: PALB2 Transcript: NM_024675.4

Final call

VUS

PM2 supporting BP1 supporting

Variant details

Gene

PALB2

Transcript

NM_024675.4

Protein

NP_078951.2:p.(Glu990Asp)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 (Supporting): absent from gnomAD v4 (AF = 0), below the VCEP's <=1/300,000 (0.000333%) frequency threshold.

2

BP1 (Supporting): the VCEP applies BP1 to all missense variants, and c.2970A>T is a confirmed missense change (p.Glu990Asp).

3

Overall: VUS — Rule 31, conflicting evidence combining one Pathogenic.Supporting (PM2) and one Benign.Supporting (BP1) criterion.

Final determination: Rule31 of the ClinGen HBOC VCEP PALB2 v1.2 criteria-combination framework (>=1 Benign.Supporting AND >=1 Pathogenic.Supporting) is satisfied by BP1 supporting and PM2 supporting, which maps to Uncertain Significance - Conflicting Evidence, i.e. VUS.

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	Not met	Not met: missense substitution with no protein length change and no predicted splice impact (SpliceAI max delta 0.026, below the 0.2 threshold).	cspec pvs1_variant_assessment pvs1_gene_context spliceai
PS1	Not met	Not met: no predicted splice impact (SpliceAI max delta 0.026), so the VCEP's splicing-based PS1 does not apply.	cspec clinvar spliceai pm5_candidates
PS2	N/A	Not applicable: the PALB2 VCEP bars PS2 because informative de novo occurrences have not been observed for this disease.	cspec
PS3	N/A	Not applicable: the PALB2 VCEP does not use PS3, and no variant-specific functional assay data were available.	cspec oncokb
PS4	Not assessed	Not assessed: no case-control or prevalence data existed to evaluate enrichment (threshold OR >=3, p <=0.05).	cspec
PM1	N/A	Not applicable: the PALB2 VCEP does not use PM1; no VCEP-approved critical domain list exists for this gene.	cspec
PM2	Met	Met (Supporting): absent from gnomAD v4 (AF=0), satisfying the VCEP frequency threshold of <=1/300,000 (0.000333%).	cspec gnomad_v4 gnomad_v2 gnomad_canada
PM3	Not assessed	Not assessed: no proband, allele, or phase observations existed, so no Fanconi anemia PM3 points could be assigned.	cspec clinvar
PM4	N/A	Not applicable: the variant is missense, not an in-frame indel or stop-loss, the only allele classes the VCEP considers under PM4.	cspec
PM5	N/A	Not applicable: the VCEP limits PM5 to truncating variants upstream of p.Tyr1183; this missense does not qualify.	cspec pm5_candidates
PM6	N/A	Not applicable: the PALB2 VCEP bars PM6 because informative de novo occurrences have not been observed for this disease.	cspec
PP1	Not assessed	Not assessed: no pedigree, LOD, or segregation data existed (Supporting requires LOD >=0.3), pending family studies.	cspec clinvar
PP2	N/A	Not applicable: the PALB2 VCEP does not use PP2.	cspec
PP3	Not met	Not met: SpliceAI max delta 0.026 is below the VCEP's 0.2 threshold, and missense in-silico predictors are barred for PP3.	cspec spliceai
PP4	N/A	Not applicable: the PALB2 VCEP does not use PP4 because the phenotype is not specific to a single genetic etiology.	cspec
PP5	N/A	Not applicable: the PALB2 VCEP does not use PP5, and ClinVar has no expert-panel classification for this variant.	cspec clinvar
BA1	Not met	Not met: absent from gnomAD v4 (AF=0), below the VCEP BA1 threshold of >0.1%.	cspec gnomad_v4 gnomad_v2 gnomad_canada
BS1	Not met	Not met: absent from gnomAD v4 (AF=0), below the VCEP BS1 threshold of >0.01%.	cspec gnomad_v4 gnomad_v2 gnomad_canada
BS2	Not met	Not met: no observed instances in healthy adults, so 0 BS2 points accrued (>=4 required for Strong).	cspec clinvar gnomad_v4 gnomad_v2 gnomad_canada
BS3	N/A	Not applicable: the PALB2 VCEP does not use BS3, and no assay demonstrating normal protein function was available.	cspec oncokb
BS4	Not assessed	Not assessed: no pedigree or segregation data existed to test lack of segregation (LOD <=-0.32 at Supporting).	cspec clinvar
BP1	Met	Met (Supporting): the VCEP applies BP1 to all missense variants; this is a confirmed missense change (p.Glu990Asp).	cspec
BP2	N/A	Not applicable: the PALB2 VCEP does not use BP2.	cspec
BP3	N/A	Not applicable: the variant is missense, not an in-frame deletion, and PALB2 has no repetitive regions of unknown function.	cspec
BP4	N/A	Not applicable: the VCEP bars BP4 for missense variants, even though SpliceAI 0.026 would satisfy the splice threshold.	cspec spliceai
BP5	N/A	Not applicable: the PALB2 VCEP does not use BP5 because PALB2's moderate penetrance allows frequent co-occurrence.	cspec
BP6	N/A	Not applicable: the PALB2 VCEP does not use BP6, and ClinVar has no expert-panel classification for this variant.	cspec clinvar
BP7	N/A	Not applicable: the variant is missense, not synonymous or deep intronic, the allele classes BP7 covers.	cspec

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.