LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Variant classification summary
NM_024675.4:c.110G>A
PALB2
· NP_078951.2:p.(Arg37His)
· NM_024675.4
GRCh37: chr16:23649272 C>T
·
GRCh38: chr16:23637951 C>T
Gene:
PALB2
Transcript:
NM_024675.4
Final call
VUS
PS4 strong
BP1 supporting
Variant details
Gene
PALB2
Transcript
NM_024675.4
Protein
NP_078951.2:p.(Arg37His)
gnomAD AF
3.905547737571989e-05 (v4.1)
ClinVar
Uncertain significance
OncoKB
Likely Neutral
Classification rationale
Interpretation summary
Generated evidence synthesis
1
PS4 Strong supports pathogenicity because the case-control comparison meets the VCEP thresholds with OR 86.22 and p=0.0118.
2
BP1 Supporting applies because c.110G>A is a missense variant producing p.Arg37His.
Final determination:
Under the PALB2 VCEP Version 1.3 ACMG/AMP combination rules, PS4 Strong alone and BP1 Supporting alone satisfy no final pathogenic or benign rule, so the call 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.110G>A is a missense p.Arg37His variant, whereas the PALB2 PVS1 rule applies to specified null-variant classes. |
cspec
vcep_palb2_pvs1_v1_3
|
| PS1 | N/A | Not applicable: PALB2's PS1 rule excludes missense changes because missense disease mechanism is not yet confirmed. |
cspec
vcep_palb2_ps1_1_3
|
| PS2 | N/A | Not applicable: the PALB2 VCEP explicitly marks PS2 as Not Applicable. |
cspec
|
| PS3 | N/A | Not applicable: the PALB2 VCEP Version 1.3 explicitly designates PS3 as not applicable for this framework. |
cspec
|
| PS4 | Met | Met: case-control comparison gives OR 86.22 (95% CI 11.87–625.98) and Fisher p=0.0118, satisfying the VCEP thresholds OR ≥3 and p≤0.05. |
cspec
PMID:23935836
gnomad_v4
PMID:28319063
|
| PM1 | N/A | Not applicable: the PALB2 VCEP excludes PM1 because missense pathogenic variation is not yet confirmed as a disease mechanism. |
cspec
|
| PM2 | Not met | Not met: the highest gnomAD v4.1 subpopulation AF is 0.0000668568, above the VCEP PM2 cutoff of 0.00000333. |
cspec
gnomad_v2
gnomad_v4
|
| PM3 | Not assessed | Not assessed: no Fanconi Anemia PM3-table entry or confirmed pathogenic variant in trans was available for c.110G>A, p.Arg37His, or p.R37H. |
cspec
vcep_palb2_pm3_bs2_1_3
PMID:23935836
PMID:28319063
|
| PM4 | N/A | Not applicable: the PALB2 VCEP CSPEC entry explicitly marks PM4 as Not Applicable for this framework. |
cspec
|
| PM5 | N/A | Not applicable: PM5 Supporting is limited to truncating variants upstream of p.His1184 and excludes missense changes. |
cspec
|
| PM6 | N/A | Not applicable: the PALB2 VCEP explicitly marks PM6 as Not Applicable. |
cspec
|
| PP1 | Not assessed | Not assessed: one family occurrence is reported, but no affected-relative count, meioses, LOD, or Bayes factor is available for the VCEP thresholds. |
cspec
PMID:23935836
|
| PP2 | N/A | Not applicable: the PALB2 VCEP excludes PP2 because missense is not yet confirmed or refuted as a disease mechanism. |
cspec
|
| PP3 | Not met | Not met: SpliceAI maximum delta score is 0.006, below the PALB2 VCEP PP3 threshold of ≥0.2 for predicted splice impact. |
cspec
spliceai
|
| PP4 | N/A | Not applicable: the VCEP excludes PP4 for dominant PALB2 cancer because breast-cancer features cannot distinguish hereditary from sporadic disease. |
cspec
|
| PP5 | N/A | Not applicable: the PALB2 VCEP explicitly recommends that PP5 not be used for this variant or any case. |
cspec
|
| BA1 | Not met | Not met: gnomAD v4.1 grpmax FAF is 0.003424%, below the VCEP BA1 threshold of >0.1%. |
cspec
gnomad_v2
gnomad_v4
|
| BS1 | Not met | Not met: gnomAD v2.1 grpmax FAF is 0.004412%, below the VCEP BS1 threshold of >0.01%. |
cspec
gnomad_v2
gnomad_v4
|
| BS2 | Not assessed | Not assessed: the only exact-variant cohort report is an affected cancer-family observation, not qualifying healthy-adult BS2 evidence. |
cspec
vcep_palb2_pm3_bs2_1_3
PMID:23935836
|
| BS3 | N/A | Not applicable: the PALB2 VCEP Version 1.3 explicitly designates BS3 as not applicable for this framework. |
cspec
|
| BS4 | Not assessed | Not assessed: the report lacks informative non-segregating relatives and provides no LOD or Bayes factor to meet any BS4 threshold. |
cspec
PMID:23935836
|
| BP1 | Met | Met, Supporting: the PALB2 VCEP BP1 rule applies to all missense variants, and c.110G>A produces p.Arg37His. |
cspec
|
| BP2 | N/A | Not applicable: the ClinGen PALB2 VCEP Version 1.3 explicitly marks BP2 as not applicable. |
cspec
|
| BP3 | N/A | Not applicable: the PALB2 VCEP CSPEC entry explicitly marks BP3 as Not Applicable for this framework. |
cspec
|
| BP4 | N/A | Not applicable: the PALB2 VCEP excludes missense variants from BP4, and c.110G>A produces the missense change p.Arg37His. |
cspec
|
| BP5 | N/A | Not applicable: the VCEP excludes BP5 because PALB2 moderate penetrance and multiple pathogenic variants make alternate molecular-basis evidence unreliable. |
cspec
|
| BP6 | N/A | Not applicable: the PALB2 VCEP explicitly recommends that BP6 not be used for this variant or any case. |
cspec
|
| BP7 | N/A | Not applicable: BP7 is limited to synonymous or deep intronic variants, whereas c.110G>A is the missense variant p.Arg37His. |
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.