LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Variant classification summary
NM_024675.4:c.205C>T
PALB2
· NP_078951.2:p.(His69Tyr)
· NM_024675.4
GRCh37: chr16:23649177 G>A
·
GRCh38: chr16:23637856 G>A
Gene:
PALB2
Transcript:
NM_024675.4
Final call
VUS
BP1 supporting benign
Variant details
Gene
PALB2
Transcript
NM_024675.4
Protein
NP_078951.2:p.(His69Tyr)
gnomAD AF
1.2424011638814102e-06 (v4.1)
ClinVar
Uncertain significance
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
NM_024675.4:c.205C>T (p.His69Tyr) is a missense variant in PALB2 exon 3. Under the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel specification for PALB2 v1.2.0, missense variants are not a confirmed mechanism of disease.
2
BP1_Supporting is met: the VCEP applies BP1 to all PALB2 missense variants given the very low likelihood that missense variants are pathogenic.
3
PM2_Supporting is not applied: while the overall gnomAD v4.1 frequency (0.000124%) is below the VCEP threshold (≤0.000333%), the variant is observed in the East Asian subpopulation at 0.00223% (1/44,858 alleles), triggering the VCEP exception for under-represented sub-populations with frequency >0.0003%.
4
The variant is present in gnomAD v4.1 at extremely low frequency (2/1,609,786 alleles; 0 homozygotes). It is absent from gnomAD v2.1.
5
This variant has been reported in ClinVar (ID 245654) as Uncertain significance by 6 clinical laboratories and Likely benign by 2 clinical laboratories. No expert panel classification is available.
6
SpliceAI predicts no splicing impact (max delta score 0.00). REVEL (0.053) and BayesDel (-0.387659) are consistent with a benign computational prediction, though in silico predictors are not used for PALB2 missense variants under this VCEP.
7
Multiple criteria are not applicable under the PALB2 VCEP for missense variants: PVS1 (not a null variant), PS1 (missense excluded), PM1 (missense pathogenicity not confirmed), PM5 (missense excluded), PP2 (missense not confirmed), PP3 (missense excluded), BP4 (missense excluded), BP7 (missense excluded). PS2, PM6, PS3, BS3, PP4, PP5, BP2, BP5, BP6 are not applicable per VCEP specification.
8
No variant-specific functional, segregation, case-control, or Fanconi Anemia proband data were identified in the reviewed literature or databases.
Final determination:
No criteria-combination rule matched the adjudicated criteria in the Richards et.al., 2015 - Combining rules v1.2.0 framework, so the variant remains a Variant of Uncertain Significance pending human review.
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 | N/A | NM_024675.4:c.205C>T is a missense variant (p.His69Tyr). The PALB2 VCEP PVS1 decision tree (v1.2.0) applies to null variants (nonsense, frameshift, canonical splice). Generic PVS1 framework confirms this variant falls outside null-variant buckets. |
pvs1_gene_context
pvs1_variant_assessment
cspec
|
| PS1 | N/A | PALB2 VCEP PS1 specifies 'Missense: Do not use. Missense changes are not yet confirmed as a mechanism of disease for PALB2.' PS1 under this VCEP is restricted to splicing variants via the PALB2 PS1 Splicing table (PMID:37352859). |
cspec
|
| PS2 | N/A | PALB2 VCEP specifies PS2 as not applicable: 'Do not use for AD or AR disease: Informative de novo occurrences have not yet been observed.' |
cspec
|
| PS3 | N/A | PALB2 VCEP specifies PS3 as not applicable for protein-level functional assays. Functional assessment for PALB2 missense variants is directed to RNA-level evidence under PVS1/BP7 frameworks. |
cspec
|
| PS4 | Not met | No case-control study meeting the PALB2 VCEP threshold (p≤0.05 and OR≥3 or lower 95% CI≥1.5) was identified for this variant. The variant has been observed in ClinVar with 6 laboratories reporting VUS and 2 reporting likely benign, but proband counting alone is insufficient under the VCEP which requires calibrated case-control data. |
clinvar
cspec
|
| PS5 | N/A | PS5 is not a recognized criterion in the ACMG/AMP 2015 framework (PMID:25741868) or the PALB2 VCEP v1.2.0 specification. |
|
| PM1 | N/A | PALB2 VCEP specifies PM1 as not applicable: 'Do not use: Missense pathogenic variation in PALB2 is not yet confirmed as a mechanism of disease.' |
cspec
|
| PM2 | Not met | The variant is present in gnomAD v4.1 at very low frequency (AF=0.000124%, 2/1,609,786 alleles), which is below the PALB2 VCEP PM2_Supporting threshold of ≤0.000333%. However, the variant is observed in the East Asian subpopulation at AF=0.00223% (1/44,858 alleles), which triggers the VCEP exception for under-represented sub-populations with n=1 but frequency >0.0003%. PM2 is therefore not applied. |
gnomad_v4
cspec
|
| PM5 | N/A | PALB2 VCEP PM5 specifies: 'Do not use for missense changes: Missense changes are not yet confirmed as a mechanism of disease for PALB2.' The applicable PM5 rule is restricted to frameshifting/truncating variants upstream of p.Tyr1183 and splice variants, which does not apply to this missense variant. |
cspec
pm5_candidates
|
| PM6 | N/A | PALB2 VCEP specifies PM6 as not applicable: 'Do not use for AD or AR disease: Informative de novo occurrences have not yet been observed.' |
cspec
|
| PP1 | Not met | No co-segregation data (LOD scores, Bayes factors, or affected relative counts) were identified for this variant. The PALB2 VCEP requires quantitative co-segregation analysis; no such data are available. |
cspec
|
| PP2 | N/A | PALB2 VCEP specifies PP2 as not applicable: 'Do not use. Missense is not yet confirmed or refuted as a mechanism of disease for PALB2.' |
cspec
|
| PP3 | N/A | PALB2 VCEP PP3 specifies: 'Missense: Do not use.' PP3 under this VCEP is restricted to splicing variants with SpliceAI ≥0.2. This is a missense variant (p.His69Tyr). REVEL score is 0.053 and BayesDel score is -0.387659, both consistent with a benign in silico prediction, but computational predictors are not used for PALB2 missense variants under this VCEP. |
cspec
spliceai
revel
bayesdel
|
| PP4 | N/A | PALB2 VCEP specifies PP4 as not applicable: breast cancer has multiple genetic etiologies and no features readily distinguish hereditary from sporadic causes under this criterion. |
cspec
|
| PP5 | N/A | PALB2 VCEP specifies PP5 as 'Not Applicable for this VCEP' per ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation. |
cspec
|
| BA1 | Not met | The variant does not meet the PALB2 VCEP BA1 threshold of Grpmax Filtering AF >0.1% in gnomAD v4. The total allele frequency is 0.000124% (2/1,609,786 alleles). Grpmax filtering AF is not available, but even the highest subpopulation frequency (East Asian, 0.00223%) is well below the 0.1% threshold. |
gnomad_v4
cspec
|
| BS1 | Not met | The variant does not meet the PALB2 VCEP BS1 threshold of Grpmax Filtering AF >0.01% in gnomAD v4. The highest subpopulation frequency (East Asian) is 0.00223%, below the 0.01% threshold. |
gnomad_v4
cspec
|
| BS2 | Not met | No Fanconi Anemia proband data are available to assign BS2 points under the PALB2 VCEP BS2 tables. BS2 requires observation in healthy individuals with specific Fanconi Anemia phenotypic context, which is absent from the available evidence. |
cspec
|
| BS3 | N/A | PALB2 VCEP specifies BS3 as not applicable for protein-level functional studies. Benign functional evidence for PALB2 missense variants is assessed under the BP7(RNA) framework. |
cspec
|
| BS4 | Not met | No quantitative co-segregation data (LOD scores or Bayes factors) demonstrating lack of segregation are available for this variant. The PALB2 VCEP mandates quantitative analysis for BS4 assessment. |
cspec
|
| BP1 | Met | PALB2 VCEP BP1 specifies application to all missense variants in PALB2. Based on published and unpublished functional studies, PALB2 has a low rate of missense variants that are non-functional in relevant assays, and true pathogenic missense variants are thought to be exceedingly rare. |
cspec
|
| BP2 | N/A | PALB2 VCEP specifies BP2 as not applicable. |
cspec
|
| BP4 | N/A | PALB2 VCEP BP4 specifies: 'Missense: Do not use.' BP4 under this VCEP is restricted to splicing variants with SpliceAI ≤0.1. This is a missense variant (p.His69Tyr). |
cspec
spliceai
|
| BP5 | N/A | PALB2 VCEP specifies BP5 as not applicable: cases with multiple pathogenic variants have been observed in PALB2 with no noticeable phenotypic difference, and PALB2 moderate penetrance means co-occurrence with other pathogenic variants is not informative. |
cspec
|
| BP6 | N/A | PALB2 VCEP specifies BP6 as 'Not Applicable for this VCEP' per ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation. |
cspec
|
| BP7 | N/A | PALB2 VCEP BP7 applies to synonymous and deep intronic variants. The Supporting strength rule specifies: 'Use for synonymous and deep intronic variants defined as further than (but not including) +7 and further than (but not including) -21 at donor and acceptor sites.' This is a missense variant (p.His69Tyr). |
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.