LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Variant classification summary
NM_024675.4:c.2488del
PALB2
· NP_078951.2:p.(Glu830SerfsTer21)
· NM_024675.4
GRCh37: chr16:23640986 TC>T
·
GRCh38: chr16:23629665 TC>T
Gene:
PALB2
Transcript:
NM_024675.4
Final call
Likely Pathogenic
PVS1 very strong
PM5 supporting
Variant details
Gene
PALB2
Transcript
NM_024675.4
Protein
NP_078951.2:p.(Glu830SerfsTer21)
gnomAD AF
5.57580053007277e-06 (v4.1)
ClinVar
Pathogenic
OncoKB
Likely Oncogenic
Classification rationale
Interpretation summary
Generated evidence synthesis
1
Likely Pathogenic: PVS1 (very strong) is supported by the exon-5 frameshift's premature stop at residue 850, upstream of the VCEP His1184 boundary.
2
Likely Pathogenic: PM5 (supporting) applies because the NMD-prone truncation occurs upstream of p.His1184 with PVS1 at very strong strength.
Final determination:
Rule19 of the PALB2 VCEP Version 1.3 framework classifies a variant as Likely Pathogenic when one very strong pathogenic criterion and one supporting pathogenic criterion are satisfied.
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-5 frameshift creates a premature stop at residue 850, upstream of the VCEP's His1184 PVS1 boundary, with no downgrade rule applying. |
cspec
vcep_palb2_pvs1_v1_3
pvs1_variant_assessment
|
| PS1 | N/A | Not applicable: c.2488del is a frameshift, while PALB2 PS1 is restricted to missense-excluded and splicing-table pathways. |
cspec
vcep_palb2_ps1_1_3
|
| PS2 | N/A | Not applicable: the PALB2 VCEP specification explicitly marks PS2 as not applicable. |
cspec
|
| PS3 | N/A | Not applicable: the PALB2 VCEP v1.3 explicitly designates PS3 as not applicable, so functional assay evidence cannot receive PS3. |
cspec
PMID:17200671
|
| PS4 | Not assessed | Not assessed: aggregate PALB2 truncating variants met OR 4.69 and p=6.9×10⁻⁶ thresholds, but c.2488del was not variant-specific in that study. |
cspec
PMID:28779002
|
| PM1 | N/A | Not applicable: the PALB2 VCEP CSPEC explicitly marks PM1 as Not Applicable, with no PALB2 domain table supplied. |
cspec
|
| PM2 | Not met | Not met: the highest gnomAD v4.1 subpopulation frequency is 0.0098799%, exceeding the PALB2 PM2 threshold of 0.000333%. |
cspec
gnomad_v4
gnomad_v2
|
| PM3 | Not assessed | Not assessed: the VCEP PM3 table has no c.2488del entry, and no affected-proband phase evidence assigns any PM3 points. |
cspec
vcep_palb2_pm3_bs2_1_3
PMID:17200671
|
| PM4 | N/A | Not applicable: the PALB2 Version 1.3 CSPEC explicitly marks PM4 as Not Applicable. |
cspec
|
| PM5 | Met | Met at Supporting: the frameshift terminates before p.His1184, satisfying the VCEP PM5 truncation cutoff, subject to confirming PVS1 Very Strong. |
cspec
vcep_palb2_pvs1_v1_3
pvs1_variant_assessment
|
| PM6 | N/A | Not applicable: the PALB2 VCEP specification explicitly marks PM6 as not applicable. |
cspec
|
| PP1 | Not assessed | Not assessed: no variant-specific LOD, Bayes factor, or confirmed affected-relative segregation is available for c.2488del against the VCEP PP1 thresholds. |
cspec
PMID:25099575
|
| PP2 | N/A | Not applicable: the PALB2 VCEP CSPEC explicitly marks PP2 as Not Applicable. |
cspec
|
| PP3 | N/A | Not applicable: PALB2 PP3 covers silent, missense/in-frame, and specified intronic variants, whereas c.2488del is a frameshift. |
cspec
|
| PP4 | N/A | Not applicable: the VCEP excludes PP4 for hereditary breast cancer because genetic heterogeneity prevents a phenotype specific to one genetic etiology. |
cspec
|
| PP5 | N/A | Not applicable: the VCEP explicitly prohibits PP5, regardless of the available pathogenic ClinVar assertions. |
cspec
|
| BA1 | Not met | Not met: gnomAD v4.1 grpmax FAF is 0.005136%, below the PALB2 VCEP BA1 threshold of >0.1%. |
cspec
gnomad_v4
|
| BS1 | Not met | Not met: gnomAD v4.1 grpmax FAF is 0.005136%, below the PALB2 VCEP BS1 threshold of >0.01%. |
cspec
gnomad_v4
|
| BS2 | Not assessed | Not assessed: no qualifying healthy-adult observation was available, and the VCEP excludes gnomAD population cohorts from BS2. |
cspec
vcep_palb2_pm3_bs2_1_3
|
| BS3 | N/A | Not applicable: the PALB2 VCEP v1.3 explicitly designates BS3 as not applicable, so functional assay evidence cannot receive BS3. |
cspec
PMID:17200671
|
| BS4 | Not assessed | Not assessed: no variant-specific non-segregation result, LOD, or Bayes factor is available for the VCEP BS4 thresholds. |
cspec
|
| BP1 | N/A | Not applicable: BP1 applies to missense variants, whereas c.2488del is a frameshift. |
cspec
pvs1_variant_assessment
|
| BP2 | N/A | Not applicable: the PALB2 VCEP Version 1.3 CSPEC explicitly marks BP2 not applicable. |
cspec
|
| BP3 | N/A | Not applicable: the PALB2 Version 1.3 CSPEC explicitly marks BP3 as Not Applicable. |
cspec
|
| BP4 | N/A | Not applicable: BP4's no-splice-impact pathway cannot negate the truncating effect of this frameshift, regardless of its SpliceAI score. |
cspec
|
| BP5 | N/A | Not applicable: the VCEP prohibits BP5 because PALB2 moderate penetrance and observed multiple pathogenic variants undermine this criterion's use. |
cspec
|
| BP6 | N/A | Not applicable: the VCEP explicitly prohibits BP6, regardless of any reputable-source benign assertion. |
cspec
|
| BP7 | N/A | Not applicable: BP7 covers synonymous and specified deep-intronic variants, whereas c.2488del is a coding frameshift. |
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.