LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Variant classification summary
NM_024675.4:c.1597A>G
PALB2
· NP_078951.2:p.(Thr533Ala)
· NM_024675.4
GRCh37: chr16:23646270 T>C
·
GRCh38: chr16:23634949 T>C
Gene:
PALB2
Transcript:
NM_024675.4
Final call
VUS
BP1 supporting
Variant details
Gene
PALB2
Transcript
NM_024675.4
Protein
NP_078951.2:p.(Thr533Ala)
gnomAD AF
4.336878835039998e-06 (v4.1)
ClinVar
Uncertain significance
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
BP1 supporting: the PALB2 VCEP applies BP1 to all missense variants, including p.Thr533Ala.
Final determination:
Under the PALB2 Version 1.3 VCEP ACMG/AMP combination rules, BP1 supporting alone satisfies neither a pathogenic nor a benign rule, so the result is VUS.
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 | Not applicable: c.1597A>G is an exon 4 missense SNV, whereas the PALB2 PVS1 rule is limited to specified null variant classes. |
cspec
pvs1_variant_assessment
vcep_palb2_pvs1_v1_3
|
| PS1 | N/A | Not applicable: the PALB2 VCEP explicitly says not to use PS1 for missense changes, and this variant is p.Thr533Ala. |
cspec
vcep_palb2_ps1_1_3
pvs1_variant_assessment
|
| PS2 | N/A | Not applicable: the PALB2 VCEP explicitly designates PS2 as Not Applicable. |
cspec
|
| PS3 | N/A | Not applicable: the PALB2 VCEP Version 1.3 explicitly marks PS3 as not applicable. |
cspec
|
| PS4 | Not assessed | Not assessed: the available case-control study analyzed PALB2 variants in aggregate and reported no variant-specific p-value, effect estimate, or confidence interval for c.1597A>G. |
cspec
PMID:33471991
|
| PM1 | N/A | Not applicable: the PALB2 VCEP CSPEC marks PM1 as Not Applicable, with no approved PALB2 domain table supplied. |
cspec
|
| PM2 | Not met | Not met: the highest gnomAD v2.1 non-cancer subpopulation AF is 0.00328%, above the VCEP PM2 threshold of 0.000333%. |
cspec
gnomad_v2
gnomad_v4
|
| PM3 | Not assessed | Not assessed: no Fanconi Anemia proband, pathogenic variant in trans, or phase evidence was available to assign PALB2 VCEP PM3 points. |
cspec
vcep_palb2_pm3_bs2_1_3
|
| PM4 | N/A | Not applicable: the PALB2 VCEP CSPEC entry explicitly designates PM4 as Not Applicable for this framework. |
cspec
|
| PM5 | N/A | Not applicable: PM5 is restricted to PVS1 Very Strong NMD-prone truncating variants, whereas this variant is missense p.Thr533Ala. |
cspec
pm5_candidates
pvs1_variant_assessment
|
| PM6 | N/A | Not applicable: the PALB2 VCEP explicitly designates PM6 as Not Applicable. |
cspec
|
| PP1 | Not assessed | Not assessed: no affected-relative segregation, meioses, LOD, or Bayes factor is documented for the variant. |
cspec
|
| PP2 | N/A | Not applicable: the PALB2 VCEP CSPEC explicitly marks PP2 as Not Applicable. |
cspec
|
| PP3 | Not met | Not met: SpliceAI maximum delta score is 0.032, below the VCEP PP3 threshold of ≥0.2 for predicted splice impact in missense variants. |
cspec
spliceai
|
| PP4 | N/A | Not applicable: the PALB2 VCEP excludes PP4 for autosomal dominant breast cancer because its phenotype is not sufficiently specific to distinguish hereditary from sporadic disease. |
cspec
|
| PP5 | N/A | Not applicable: the PALB2 VCEP explicitly prohibits PP5, regardless of external reports describing this variant as pathogenic. |
cspec
|
| BA1 | Not met | Not met: gnomAD v4.1 grpmax FAF is 0.000183%, below the VCEP BA1 threshold of greater than 0.1%. |
cspec
gnomad_v4
|
| BS1 | Not met | Not met: gnomAD v4.1 grpmax FAF is 0.000183%, below the VCEP BS1 threshold of greater than 0.01%. |
cspec
gnomad_v4
|
| BS2 | Not assessed | Not assessed: gnomAD is excluded for BS2, and no qualifying clinical healthy-adult observation with the VCEP's required data is available. |
cspec
vcep_palb2_pm3_bs2_1_3
|
| BS3 | N/A | Not applicable: the PALB2 VCEP Version 1.3 explicitly marks BS3 as not applicable. |
cspec
|
| BS4 | Not assessed | Not assessed: no informative non-segregation, LOD, or Bayes factor is documented for the variant. |
cspec
|
| BP1 | Met | Met, Supporting: the PALB2 VCEP applies BP1 to all missense variants, including p.Thr533Ala. |
cspec
pvs1_variant_assessment
|
| BP2 | N/A | Not applicable: the PALB2 Version 1.3 VCEP specification explicitly marks BP2 as Not Applicable. |
cspec
|
| BP3 | N/A | Not applicable: the PALB2 VCEP CSPEC entry explicitly designates BP3 as Not Applicable, and this is a missense SNV. |
cspec
|
| BP4 | N/A | Not applicable: the PALB2 VCEP explicitly excludes BP4 for missense variants, regardless of the available SpliceAI maximum delta score of 0.032. |
cspec
|
| BP5 | N/A | Not applicable: the PALB2 VCEP prohibits BP5 because co-occurring pathogenic variants are expected and may not produce a distinguishable phenotype. |
cspec
|
| BP6 | N/A | Not applicable: the PALB2 VCEP explicitly prohibits BP6, regardless of external reports describing this variant as benign. |
cspec
|
| BP7 | N/A | Not applicable: BP7 covers synonymous or deep intronic variants, whereas NM_024675.4:c.1597A>G is an exonic missense variant. |
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.