LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Variant classification summary
NM_024675.4:c.1592del
PALB2
· NP_078951.2:p.(Leu531CysfsTer30)
· NM_024675.4
GRCh37: chr16:23646274 CA>C
·
GRCh38: chr16:23634953 CA>C
Gene:
PALB2
Transcript:
NM_024675.4
Final call
Pathogenic
PVS1 very strong
PS4 strong
PP5 supporting
Variant details
Gene
PALB2
Transcript
NM_024675.4
Protein
NP_078951.2:p.(Leu531CysfsTer30)
gnomAD AF
7.187184011737415e-05 (v4.1)
ClinVar
Pathogenic
OncoKB
Likely Oncogenic
Classification rationale
Interpretation summary
Generated evidence synthesis
1
Pathogenic: PVS1 (very strong) reflects the NMD-prone exon 4 frameshift p.(Leu531CysfsTer30).
2
Pathogenic: PS4 (strong) is supported by exact-variant Finnish case-control enrichment with p=0.005 and OR=11.3.
3
Pathogenic: PP5 (supporting) is recorded from the ClinGen expert panel pathogenic classification.
Final determination:
Under Rule1 of the PALB2 Version 1.3 VCEP framework, one Pathogenic Very Strong criterion plus at least one Pathogenic Strong criterion yields Pathogenic.
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 | Met | Met, very strong: the exon 4 frameshift creates p.(Leu531CysfsTer30), a premature stop upstream of c.3301 on the clinically relevant PALB2 transcript. |
cspec
vcep_palb2_pvs1_v1_3
pvs1_variant_assessment
pvs1_gene_context
|
| PS1 | N/A | Not applicable: this frameshift is neither a missense nor a splicing variant, the only variant classes covered by PALB2 PS1 guidance. |
cspec
vcep_palb2_ps1_1_3
pvs1_variant_assessment
|
| PS2 | N/A | Not applicable: the PALB2 VCEP specification explicitly marks PS2 as not applicable. |
cspec
|
| PS3 | N/A | Not applicable: the PALB2 Version 1.3 VCEP specification explicitly marks PS3 not applicable, regardless of available functional assay evidence. |
cspec
|
| PS4 | Met | Met at Strong: Finnish case-control data reported p=0.005, OR=11.3, and 95% CI 1.8–57.8, satisfying p≤.05 and OR≥3. |
cspec
PMID:17287723
PMID:18628482
|
| PM1 | N/A | Not applicable: the PALB2 VCEP explicitly marks PM1 as Not Applicable, and no approved PALB2 domain table is supplied. |
cspec
|
| PM2 | Not met | Not met: the highest gnomAD v4.1 subpopulation AF is 0.174978% in Finnish individuals, exceeding the PALB2 VCEP PM2 threshold of 0.000333%. |
cspec
gnomad_v4
|
| PM3 | Not assessed | Not assessed: no governing-table entry or documented Fanconi-anemia observation establishes this allele in trans with a pathogenic variant. |
vcep_palb2_pm3_bs2_1_3
cspec
|
| PM4 | N/A | Not applicable: PALB2 VCEP PM4 is restricted to stop-loss variants, whereas this variant is a frameshift deletion. |
cspec
|
| PM5 | Not assessed | Not assessed: PM5 requires PVS1 at Very Strong, but the available evidence does not provide that required PVS1 strength determination. |
cspec
pvs1_variant_assessment
|
| PM6 | N/A | Not applicable: the PALB2 VCEP specification explicitly marks PM6 as not applicable. |
cspec
|
| PP1 | Not assessed | Not assessed: segregation was reported, but no VCEP-required PP1 LOD or Bayes factor was provided. |
cspec
PMID:17287723
PMID:18628482
|
| PP2 | N/A | Not applicable: the PALB2 VCEP explicitly marks PP2 as Not Applicable for this gene framework. |
cspec
|
| PP3 | N/A | Not applicable: c.1592del is an exonic frameshift, outside PP3's VCEP scope for silent, missense/in-frame, or qualifying intronic variants. |
cspec
|
| PP4 | N/A | Not applicable: the VCEP excludes PP4 for dominant PALB2 cancer predisposition because breast cancer lacks a sufficiently specific phenotype. |
cspec
|
| PP5 | Met | Not applicable: the PALB2 VCEP explicitly states that PP5 is not for use. |
cspec
clinvar
|
| BA1 | Not met | Not met: gnomAD v4.1 grpmax FAF is 6.8e-07 (0.000068%), below the PALB2 VCEP BA1 threshold of >0.1%. |
cspec
gnomad_v4
|
| BS1 | Not met | Not met: gnomAD v4.1 grpmax FAF is 6.8e-07 (0.000068%), below the PALB2 VCEP BS1 threshold of >0.01%. |
cspec
gnomad_v4
|
| BS2 | Not assessed | Not assessed: no matching entry was found in PALB2_PM3_BS2_1.3.pdf, and the VCEP excludes gnomAD population cohorts from BS2. |
cspec
vcep_palb2_pm3_bs2_1_3
gnomad_v4
|
| BS3 | N/A | Not applicable: the PALB2 Version 1.3 VCEP specification explicitly marks BS3 not applicable, so no benign functional strength can be assigned. |
cspec
|
| BS4 | Not assessed | Not assessed: no VCEP-required negative-segregation LOD or Bayes factor was reported. |
cspec
PMID:17287723
PMID:18628482
|
| BP1 | N/A | Not applicable: BP1 is limited to missense variants, whereas this variant is a frameshift at p.Leu531CysfsTer30. |
cspec
pvs1_variant_assessment
|
| BP2 | N/A | Not applicable: the PALB2 VCEP explicitly designates BP2 as Not Applicable. |
cspec
|
| BP3 | N/A | Not applicable: PALB2 VCEP BP3 is not used for small in-frame losses or repetitive regions, and this variant is a frameshift. |
cspec
|
| BP4 | N/A | Not applicable: c.1592del is a truncating frameshift, so SpliceAI max delta 0.029 cannot establish BP4's no-impact conclusion. |
cspec
|
| BP5 | N/A | Not applicable: the PALB2 VCEP explicitly instructs that BP5 should not be used for this disorder. |
cspec
|
| BP6 | N/A | Not applicable: the PALB2 VCEP explicitly states that BP6 is not for use. |
cspec
|
| BP7 | N/A | Not applicable: c.1592del is an exonic frameshift, 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.