LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Variant classification summary
NM_024675.3:c.871G>A
PALB2
· NP_078951.2:p.(Ala291Thr)
· NM_024675.3
GRCh37: chr16:23646996 C>T
·
GRCh38: chr16:23635675 C>T
Gene:
PALB2
Transcript:
NM_024675.3
Final call
PM2 supporting
BP1 supporting
Variant details
Gene
PALB2
Transcript
NM_024675.3
Protein
NP_078951.2:p.(Ala291Thr)
gnomAD AF
0.0 (v4.1)
ClinVar
Uncertain Significance
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
The PALB2 NM_024675.3:c.871G>A (NP_078951.2:p.(Ala291Thr), p.(A291T)) variant has been reported in ClinVar, where the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel classified it as uncertain significance.
2
This variant is absent from gnomAD v4.1 (0/1613968 alleles; AF 0%), which is below the PALB2 PM2_Supporting threshold of 0.000333% and far below the BS1 and BA1 benign frequency thresholds.
3
SpliceAI predicts no significant splice impact (max delta score 0.00), and available computational scores are low for missense deleteriousness (REVEL 0.068; BayesDel -0.616818); under the PALB2 specification, PP3 and BP4 are not used for missense variants, while BP1 applies to all missense variants.
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 | Not met | This missense variant does not fall into the PALB2 loss-of-function PVS1 framework, and SpliceAI predicts no significant splice impact (max delta score 0.00), so PVS1 is not supported. |
cspec
pvs1_gene_context
pvs1_variant_assessment
spliceai
|
| PS1 | Not met | No evidence was identified that this variant produces the same RNA effect as an established pathogenic PALB2 variant, and no splice effect is predicted, so PS1 is not supported. |
cspec
spliceai
|
| PS2 | N/A | The PALB2 specification does not use PS2 for this framework. |
cspec
|
| PS3 | N/A | The PALB2 specification does not use PS3 in this framework, and no variant-specific functional assay evidence was identified. |
cspec
oncokb
|
| PS4 | Not assessed | No case-control study or exact-variant enrichment data were identified to show that this variant is significantly more common in affected individuals than in controls, so PS4 cannot be applied. |
cspec
gnomad_v4
clinvar
|
| PM1 | N/A | The PALB2 specification does not use PM1 for this framework. |
cspec
|
| PM2 | Met | This variant is absent from gnomAD v4.1 (0/1613968 alleles, AF 0%), which is below the PALB2 PM2_Supporting threshold of 1/300,000 (0.000333%), so PM2_Supporting is met. |
cspec
gnomad_v4
|
| PM3 | Not assessed | No report was identified showing this variant in trans with a pathogenic PALB2 variant in a recessive Fanconi anemia context, so PM3 cannot be applied. |
cspec
clinvar
|
| PM4 | N/A | This is a missense substitution, and the PALB2 specification does not apply PM4 to this variant type. |
cspec
|
| PM5 | N/A | For PALB2, PM5 is a truncation-cutoff rule rather than classic same-residue missense logic, so this missense variant does not meet the PALB2 PM5 framework. |
cspec
pm5_candidates
|
| PM6 | N/A | The PALB2 specification does not use PM6 for this framework. |
cspec
|
| PP1 | Not assessed | No segregation data were identified for this variant, so PP1 cannot be applied. |
cspec
clinvar
|
| PP2 | N/A | The PALB2 specification does not use PP2 for this framework. |
cspec
|
| PP3 | N/A | For PALB2 missense variants, PP3 is not used. In addition, SpliceAI predicts no significant splice impact (max delta score 0.00, below the 0.2 threshold). |
cspec
spliceai
|
| PP4 | N/A | The PALB2 specification does not use PP4 for this framework. |
cspec
|
| PP5 | N/A | The PALB2 specification does not use PP5 for this framework. |
cspec
|
| BA1 | Not met | This variant is absent from gnomAD v4.1 (AF 0%), which is below the PALB2 BA1 threshold of greater than 0.1%, so BA1 is not met. |
cspec
gnomad_v4
|
| BS1 | Not met | This variant is absent from gnomAD v4.1 (AF 0%), which is below the PALB2 BS1 threshold of greater than 0.01%, so BS1 is not met. |
cspec
gnomad_v4
|
| BS2 | Not assessed | No point-based evidence in unaffected individuals was identified for this variant, so BS2 cannot be applied. |
cspec
clinvar
|
| BS3 | N/A | The PALB2 specification does not use BS3 for this framework. |
cspec
|
| BS4 | Not assessed | No non-segregation data or quantitative evidence against cosegregation were identified for this variant, so BS4 cannot be applied. |
cspec
clinvar
|
| BP1 | Met | This is a missense variant, and the PALB2 specification applies BP1_Supporting to all missense variants, so BP1 is met at supporting strength. |
cspec
|
| BP2 | N/A | The PALB2 specification does not use BP2 for this framework. |
cspec
|
| BP3 | N/A | The PALB2 specification does not use BP3 for this framework. |
cspec
|
| BP4 | N/A | For PALB2 missense variants, BP4 is not used. SpliceAI also predicts no significant splice impact (max delta score 0.00, below the 0.1 threshold for splicing BP4). |
cspec
spliceai
|
| BP5 | N/A | The PALB2 specification does not use BP5 for this framework. |
cspec
|
| BP6 | N/A | The PALB2 specification does not use BP6 for this framework. |
cspec
|
| BP7 | N/A | This is a missense variant rather than a synonymous or qualifying deep intronic variant, so BP7 is not applicable. |
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.