LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Variant classification summary
NM_024675.4:c.2052del
PALB2
· NP_078951.2:p.(Arg686GlyfsTer23)
· NM_024675.4
GRCh37: chr16:23641422 TG>T
·
GRCh38: chr16:23630101 TG>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.(Arg686GlyfsTer23)
gnomAD AF
1.548879540540373e-05 (v4.1)
ClinVar
Pathogenic
OncoKB
Likely Oncogenic
Classification rationale
Interpretation summary
Generated evidence synthesis
1
PVS1 very strong: c.2052del creates a premature truncation in PALB2, where loss of function is an established disease mechanism.
2
PM5 supporting: p.Arg686GlyfsTer23 terminates upstream of the PALB2 VCEP p.Tyr1183 cutoff.
Final determination:
PALB2 VCEP Version 1.2 Rule19 is satisfied by one Pathogenic Very Strong criterion and one Pathogenic Supporting criterion, resulting in a Likely Pathogenic classification.
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.2052del creates p.Arg686GlyfsTer23, a premature truncation in PALB2, an established loss-of-function disease gene. |
cspec
pvs1_generic_framework
PMID:25741868
|
| PS1 | N/A | Not applicable: c.2052del is a coding frameshift, p.Arg686GlyfsTer23, rather than a same-splice-site substitution evaluated by PALB2 PS1. |
cspec
|
| PS2 | N/A | Not applicable: the PALB2 VCEP explicitly prohibits PS2 because informative de novo occurrences have not been observed. |
cspec
|
| PS3 | N/A | Not applicable: PALB2 VCEP specification version 1.2 explicitly designates PS3 as not applicable. |
cspec
|
| PS4 | Not assessed | Not assessed: the exact-variant case-control odds ratio, p-value, and lower 95% confidence bound required by the PALB2 PS4 rule are not available. |
cspec
PMID:28779002
clinvar
|
| PM1 | N/A | Not applicable: PALB2 VCEP PM1 is prohibited because missense pathogenic variation is not confirmed as a disease mechanism. |
cspec
|
| PM2 | Not met | Not met: gnomAD v4.1 total AF is 0.00154888%, above the PALB2 PM2 cutoff of <=0.000333%. |
cspec
gnomad_v4
|
| PM3 | Not assessed | Not assessed: no affected-proband observation or documented phase with a pathogenic PALB2 variant in trans is available for c.2052del. |
cspec
|
| PM4 | N/A | Not applicable: the PALB2 Version 1.2 specification explicitly excludes PM4, so this frameshift is evaluated under PVS1 instead. |
cspec
|
| PM5 | Met | Met, Supporting: p.Arg686GlyfsTer23 terminates near residue 708, upstream of the PALB2 VCEP cutoff p.Tyr1183. |
cspec
|
| PM6 | N/A | Not applicable: the PALB2 VCEP explicitly prohibits PM6 for both autosomal-dominant and autosomal-recessive disease. |
cspec
|
| PP1 | Not assessed | Not assessed: no exact-variant pedigree, affected-relative count, LOD score, or Bayes factor is available to compare with the VCEP PP1 thresholds. |
cspec
|
| PP2 | N/A | Not applicable: PALB2 VCEP PP2 is prohibited, and c.2052del is a frameshift rather than a missense variant. |
cspec
|
| PP3 | N/A | Not applicable: the frameshift consequence p.(Arg686GlyfsTer23) is outside the PALB2 VCEP PP3 splice-prediction scope. |
cspec
|
| PP4 | N/A | Not applicable: the PALB2 VCEP excludes PP4 for autosomal-dominant breast cancer because the phenotype is not sufficiently specific. |
cspec
|
| PP5 | N/A | Not applicable: PALB2 excludes PP5, and this exact variant has no ClinVar expert-panel Pathogenic or Likely pathogenic classification. |
cspec
clinvar
|
| BA1 | Not met | Not met: gnomAD v4.1 grpmax FAF is 0.001454%, below the PALB2 BA1 threshold of >0.1%. |
cspec
gnomad_v4
|
| BS1 | Not met | Not met: gnomAD v4.1 grpmax FAF is 0.001454%, below the PALB2 BS1 threshold of >0.01%. |
cspec
gnomad_v4
|
| BS2 | Not met | Not met: gnomAD v4.1 reports zero homozygotes, providing no PALB2 BS2 points toward the 1-point supporting threshold. |
cspec
gnomad_v4
|
| BS3 | N/A | Not applicable: PALB2 VCEP specification version 1.2 explicitly designates BS3 as not applicable. |
cspec
|
| BS4 | Not assessed | Not assessed: no exact-variant non-segregation data or quantitative LOD/LR result is available to compare with the VCEP BS4 thresholds. |
cspec
|
| BP1 | N/A | Not applicable: BP1 is restricted to missense variants, whereas c.2052del produces the frameshift p.Arg686GlyfsTer23. |
cspec
|
| BP2 | N/A | Not applicable: PALB2 VCEP version 1.2 explicitly designates BP2 as not applicable. |
cspec
|
| BP3 | N/A | Not applicable: PALB2 Version 1.2 excludes BP3, and this variant is a protein-truncating frameshift rather than a benign repeat-region indel. |
cspec
|
| BP4 | N/A | Not applicable: the frameshift consequence p.(Arg686GlyfsTer23) is outside the PALB2 VCEP BP4 splice-prediction scope. |
cspec
|
| BP5 | N/A | Not applicable: the PALB2 VCEP excludes BP5 because co-occurring pathogenic variants do not reliably alter the phenotype in this moderate-penetrance disorder. |
cspec
|
| BP6 | N/A | Not applicable: PALB2 excludes BP6, and no exact-variant ClinVar expert-panel Benign or Likely benign classification exists. |
cspec
clinvar
|
| BP7 | N/A | Not applicable: the frameshift consequence p.(Arg686GlyfsTer23) is not synonymous and is outside the PALB2 VCEP BP7 scope. |
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.