NM_024675.4:c.2856T>G

PALB2 · NP_078951.2:p.(Asp952Glu) · NM_024675.4

GRCh37: chr16:23634430 A>C · GRCh38: chr16:23623109 A>C

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.(Asp952Glu)

gnomAD AF

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

VUS: PM2 supporting reflects absence from gnomAD v2.1 and v4.1.

VUS: BP1 supporting reflects the PALB2 VCEP rule for missense variants.

Final determination: PALB2 VCEP Version 1.3 Rule31 combines at least one benign supporting criterion with at least one pathogenic supporting criterion and therefore yields Uncertain Significance - Conflicting Evidence, reported here as 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	N/A	Not applicable: PALB2 VCEP PVS1 is for null variants, whereas this variant is missense p.(Asp952Glu).	cspec vcep_palb2_pvs1_v1_3
PS1	N/A	Not applicable: PALB2 VCEP excludes PS1 for missense variants, and this variant is p.Asp952Glu rather than a demonstrated matching splice event.	cspec vcep_palb2_ps1_1_3
PS2	N/A	Not applicable: the PALB2 VCEP explicitly excludes PS2 because informative de novo occurrences have not been observed for either PALB2 disease context.	cspec
PS3	N/A	Not applicable: PALB2 VCEP v1.3 designates PS3 as not applicable, so no functional assay result receives PS3 strength for this variant.	cspec
PS4	Not assessed	Not assessed: PALB2 VCEP PS4 requires p <= .05 and OR/HR/RR >=3 or lower 95% CI >=1.5, but no case-control estimate is available.	cspec
PM1	N/A	Not applicable: PALB2 VCEP marks PM1 not applicable, and no approved domain-table entry or statistically significant D952 hotspot is available.	cspec
PM2	Met	Met at Supporting: gnomAD v2.1 and v4.1 report 0 observed alleles, below the PALB2 PM2 threshold of 0.000333%.	cspec gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: no affected Fanconi anemia proband, pathogenic second allele, or phase information is documented, so the VCEP PM3 point total is unavailable.	cspec vcep_palb2_pm3_bs2_1_3
PM4	N/A	Not applicable: PALB2 VCEP explicitly marks PM4 not applicable, and c.2856T>G causes missense p.(Asp952Glu), not an in-frame length change.	cspec
PM5	N/A	Not applicable: PALB2 VCEP PM5 is reserved for qualifying truncating or observed splice variants, whereas this variant is the missense change p.Asp952Glu.	cspec pm5_candidates
PM6	N/A	Not applicable: the PALB2 VCEP explicitly excludes PM6 because assumed de novo occurrences are not informative in the PALB2 disease contexts.	cspec
PP1	Not assessed	Not assessed: no family segregation data or quantitative result is available to compare with the PP1 supporting threshold of LOD ≥0.3 or LR ≥2:1.	cspec
PP2	N/A	Not applicable: PALB2 VCEP excludes PP2 because missense is not established as a disease mechanism, regardless of the REVEL score of 0.026.	cspec revel
PP3	N/A	Not applicable: the PALB2 VCEP explicitly excludes missense variants from PP3, so no computational score is evaluated.	cspec
PP4	N/A	Not applicable: the PALB2 VCEP excludes PP4 because breast cancer is genetically heterogeneous and lacks a sufficiently specific distinguishing phenotype.	cspec
PP5	N/A	Not applicable: the PALB2 VCEP excludes PP5, and exact-variant ClinVar contains only a single-laboratory Uncertain significance assertion with no expert-panel classification.	cspec clinvar
BA1	Not met	Not met: gnomAD v2.1 and v4.1 report 0 observed alleles, below the PALB2 VCEP BA1 threshold of >0.1%.	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not met: gnomAD v2.1 and v4.1 report 0 observed alleles, below the PALB2 VCEP BS1 threshold of >0.01%.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: gnomAD provides 0 observed alleles, but no qualifying healthy individual or homozygote observation is available for BS2.	cspec gnomad_v2 gnomad_v4
BS3	N/A	Not applicable: PALB2 VCEP v1.3 designates BS3 as not applicable, so no functional assay result receives BS3 strength for this variant.	cspec
BS4	Not assessed	Not assessed: no non-segregation observations or quantitative result is available to compare with the BS4 supporting threshold of LOD ≤−0.32 or LR ≤0.48.	cspec
BP1	Met	Met at supporting strength: the PALB2 VCEP applies BP1 to all missense variants, and this variant is p.Asp952Glu.	cspec
BP2	N/A	Not applicable: the PALB2 VCEP explicitly excludes BP2 and provides no applicable strength rule for this criterion.	cspec
BP3	N/A	Not applicable: PALB2 VCEP explicitly marks BP3 not applicable, and this variant is missense p.(Asp952Glu), not a repetitive-region in-frame deletion.	cspec
BP4	N/A	Not applicable: the PALB2 VCEP excludes missense variants from BP4, so REVEL and SpliceAI scores are not evaluated.	cspec
BP5	N/A	Not applicable: the PALB2 VCEP excludes BP5 because co-occurring pathogenic variants may not alter phenotype and PALB2 has moderate penetrance.	cspec
BP6	N/A	Not applicable: the PALB2 VCEP excludes BP6, and exact-variant ClinVar has no expert-panel Benign or Likely benign classification.	cspec clinvar
BP7	N/A	Not applicable: the variant changes Asp952 to Glu rather than being synonymous, whereas BP7 is limited to synonymous or qualifying deep intronic variants.	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.