LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Variant classification summary
NM_024675.4:c.886del
PALB2
· NP_078951.2:p.(Met296Ter)
· NM_024675.4
GRCh37: chr16:23646980 AT>A
·
GRCh38: chr16:23635659 AT>A
Gene:
PALB2
Transcript:
NM_024675.4
Final call
Pathogenic
PVS1 very strong
PM2 supporting
PM5 supporting
Variant details
Gene
PALB2
Transcript
NM_024675.4
Protein
NP_078951.2:p.(Met296Ter)
gnomAD AF
2.478317816998534e-06 (v4.1)
ClinVar
Pathogenic
OncoKB
Likely Oncogenic
Classification rationale
Interpretation summary
Generated evidence synthesis
1
PVS1 very strong: c.886del shifts the reading frame and creates a premature stop p.(Met296Ter) in exon 4 of 13 with predicted NMD, upstream of the p.Tyr1183 truncation boundary, in a gene where loss of function is an established disease mechanism.
2
PM2 supporting: gnomAD v4.1 total allele frequency of 0.000248% (4/1,613,998 alleles) is below the VCEP 1/300,000 (0.000333%) rarity threshold.
3
PM5 supporting: the premature stop at codon 296 lies upstream of p.Tyr1183*, the most C-terminal known pathogenic PALB2 truncation, satisfying the VCEP truncation-cutoff rule.
Final determination:
Rule 4 of the PALB2 v1.2 specification is satisfied - one very strong pathogenic criterion (PVS1) plus at least two supporting pathogenic criteria (PM2, PM5), with no met benign criterion - yielding 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 at Very Strong: c.886del creates a premature stop p.(Met296Ter) in exon 4 of 13, upstream of p.Tyr1183 with predicted NMD, per the PALB2 VCEP PVS1 decision tree. |
cspec
pvs1_generic_framework
PMID:30089731
PMID:25099575
PMID:28779002
|
| PS1 | N/A | Not applicable: c.886del is a truncating frameshift (p.Met296Ter) with no splice impact (SpliceAI 0.018); PALB2 VCEP PS1 applies only to splice variants via its splicing table. |
cspec
pm5_candidates
|
| PS2 | N/A | Not applicable: the PALB2 ClinGen specification disallows PS2 for autosomal dominant or recessive disease, and no de novo observation for c.886del exists. |
cspec
|
| PS3 | N/A | Not applicable: the ClinGen HBOC VCEP PALB2 v1.2 specification explicitly marks PS3 as a non-applicable criterion for PALB2. |
cspec
|
| PS4 | Not assessed | Not assessed: no case-control study reports c.886del individually; PALB2 truncating-variant class-level OR 4.69 (p=6.9e-6) cannot be attributed to this exact variant. |
cspec
PMID:28779002
PMID:25099575
PMID:30089731
|
| PM1 | N/A | Not applicable: the PALB2 VCEP v1.2 does not use PM1 (missense pathogenicity unconfirmed), lists no approved critical-functional domains, and c.886del is a truncating frameshift, not missense. |
cspec
|
| PM2 | Met | Met (supporting): gnomAD v4.1 total AF of 0.000248% (4/1,613,998 alleles) falls below the PALB2 VCEP PM2 threshold of 1/300,000 (0.000333%). |
cspec
gnomad_v4
gnomad_v2
gnomad_canada
|
| PM3 | Not assessed | Not assessed: no affected proband is documented with c.886del in trans with a second PALB2 pathogenic variant, and no phase or Fanconi-phenotype data exists. |
cspec
gnomad_v4
PMID:30089731
PMID:25099575
|
| PM4 | N/A | Not applicable: the PALB2 ClinGen VCEP specification v1.2 excludes PM4, and this 1-bp deletion causes a frameshift premature stop, not an in-frame protein-length change. |
cspec
|
| PM5 | Met | Met (supporting): frameshift c.886del creates a premature stop at codon 296, upstream of p.Tyr1183*, satisfying the PALB2 VCEP PM5_Supporting truncation-cutoff rule. |
cspec
pm5_candidates
PMID:30089731
PMID:25099575
|
| PM6 | N/A | Not applicable: the PALB2 ClinGen specification disallows PM6 for autosomal dominant or recessive disease, and no assumed-de-novo observation for c.886del exists. |
cspec
|
| PP1 | Not assessed | Not assessed: no segregation or LOD data for c.886del; the PALB2 specification requires LOD >=0.3 or Bayes factor >=2:1 for supporting PP1. |
cspec
|
| PP2 | N/A | Not applicable: the PALB2 VCEP v1.2 prohibits PP2 (missense mechanism not confirmed or refuted for PALB2), and c.886del is a truncating frameshift, not missense. |
cspec
|
| PP3 | N/A | Not applicable: c.886del is a frameshift deletion creating p.Met296Ter, a truncating variant outside PP3's missense/SpliceAI scope. |
cspec
PMID:30089731
PMID:25099575
|
| PP4 | N/A | Not applicable: the PALB2 VCEP v1.2 forbids PP4 for autosomal-dominant breast cancer, whose multiple genetic etiologies and lack of distinguishing features make phenotype-based support unusable. |
cspec
|
| PP5 | N/A | Not applicable: the PALB2 VCEP v1.2 declares PP5 not applicable, and ClinVar VCV000143979 has no expert-panel classification, only laboratory submissions. |
cspec
clinvar
|
| BA1 | Not met | Not met: gnomAD v4.1 grpmax filtering AF of 0.000079% is over 1,000-fold below the PALB2 VCEP BA1 threshold of >0.1%. |
cspec
gnomad_v4
gnomad_v2
|
| BS1 | Not met | Not met: gnomAD v4.1 grpmax filtering AF of 0.000079% is ~127-fold below the PALB2 VCEP BS1 threshold of >0.01%. |
cspec
gnomad_v4
gnomad_v2
|
| BS2 | Not met | Not met: gnomAD v4.1 and v2.1 report zero homozygotes (0/1,613,998 and 0/251,348 alleles) and no unaffected-carrier observations, scoring 0 BS2 points. |
cspec
gnomad_v4
gnomad_v2
gnomad_canada
|
| BS3 | N/A | Not applicable: the ClinGen HBOC VCEP PALB2 v1.2 specification explicitly marks BS3 as a non-applicable criterion for PALB2. |
cspec
|
| BS4 | Not assessed | Not assessed: no non-segregation or LOD data for c.886del; the PALB2 specification requires LOD <= -0.32 or Bayes factor <=0.48 for supporting BS4. |
cspec
|
| BP1 | N/A | Not applicable: the PALB2 VCEP BP1 supporting rule applies only to missense variants, and c.886del p.(Met296Ter) is a truncating frameshift. |
cspec
|
| BP2 | N/A | Not applicable: the PALB2 HBOP VCEP v1.2 declares BP2 not applicable, and no in-trans or in-cis observation of c.886del exists. |
cspec
|
| BP3 | N/A | Not applicable: the PALB2 ClinGen VCEP specification v1.2 excludes BP3, and the variant is a frameshift deletion, not an in-frame repeat-region indel. |
cspec
|
| BP4 | N/A | Not applicable: c.886del causes frameshift truncation (p.Met296Ter), not a missense or splice-region change, so BP4's SpliceAI no-impact path does not apply. |
cspec
PMID:30089731
PMID:25099575
|
| BP5 | N/A | Not applicable: the PALB2 VCEP v1.2 declares BP5 not applicable; co-occurring pathogenic variants are expected given moderate penetrance and do not count as benign evidence. |
cspec
|
| BP6 | N/A | Not applicable: the PALB2 VCEP v1.2 declares BP6 not applicable, and ClinVar VCV000143979 has no expert-panel benign classification (Pathogenic, laboratory submissions only). |
cspec
clinvar
|
| BP7 | N/A | Not applicable: BP7 is reserved for synonymous and deep intronic variants; c.886del is a protein-truncating frameshift (p.Met296Ter). |
cspec
PMID:30089731
PMID:25099575
|
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.