LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Variant classification summary
NM_024675.4:c.829G>A
PALB2
· NP_078951.2:p.(Asp277Asn)
· NM_024675.4
GRCh37: chr16:23647038 C>T
·
GRCh38: chr16:23635717 C>T
Gene:
PALB2
Transcript:
NM_024675.4
Final call
Likely Benign
BP1 supporting
BP4 supporting
Variant details
Gene
PALB2
Transcript
NM_024675.4
Protein
NP_078951.2:p.(Asp277Asn)
gnomAD AF
8.054782434130468e-06 (v4.1)
ClinVar
Uncertain significance
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
BP1 (Supporting): missense change (p.Asp277Asn); the PALB2 rules apply BP1 to all missense variants.
2
BP4 (Supporting): SpliceAI max delta 0.002 meets the <=0.1 threshold, indicating no predicted splice impact.
3
Overall: Likely Benign, produced by Rule19 (at least two supporting benign criteria, BP1 plus BP4).
Final determination:
PALB2 VCEP Version 1.2 Rule19 classifies a variant as Likely Benign when at least two Benign Supporting criteria are met.
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 | Not met | Not met: c.829G>A is a missense change (p.Asp277Asn), not a loss-of-function variant, with no predicted splice defect (SpliceAI max delta 0.002). |
cspec
spliceai
|
| PS1 | N/A | Not applicable: PS1 is restricted to the PALB2 splicing table, and this is a missense substitution without significant predicted splice impact. |
cspec
spliceai
|
| PS2 | N/A | Not applicable: the PALB2 expert panel specification (v1.2) designates PS2 as not applicable. |
cspec
|
| PS3 | N/A | Not applicable: the PALB2 expert panel specification (v1.2) designates PS3 as not applicable. |
cspec
PMID:25741868
|
| PS4 | Not assessed | Not assessed: no case-control study reporting this exact variant was available to test the required p<=0.05 with risk ratio >=3. |
cspec
PMID:28779002
|
| PM1 | N/A | Not applicable: the PALB2 expert panel specification (v1.2) designates PM1 as not applicable. |
cspec
|
| PM2 | Not met | Not met: gnomAD v4.1 total allele frequency 0.000805% exceeds the PM2 Supporting cutoff of <=0.000333% (1 in 300,000). |
cspec
gnomad_v4
|
| PM3 | Not assessed | Not assessed: no biallelic observations, second PALB2 variant, or phase data were available for the recessive Fanconi anemia condition. |
cspec
|
| PM4 | N/A | Not applicable: the PALB2 expert panel specification (v1.2) designates PM4 as not applicable. |
cspec
|
| PM5 | N/A | Not applicable: PM5 applies only to truncating or frameshifting variants upstream of p.Tyr1183, not to missense changes. |
cspec
spliceai
|
| PM6 | N/A | Not applicable: the PALB2 expert panel specification (v1.2) designates PM6 as not applicable. |
cspec
|
| PP1 | Not assessed | Not assessed: no segregation evidence (affected relatives, LOD score, or Bayes factor) was available. |
cspec
|
| PP2 | N/A | Not applicable: the PALB2 expert panel specification (v1.2) designates PP2 as not applicable. |
cspec
|
| PP3 | Not met | Not met: SpliceAI max delta 0.002 falls below the >=0.2 threshold required for PP3 splice evidence. |
cspec
spliceai
revel
bayesdel
|
| PP4 | N/A | Not applicable: the PALB2 expert panel specification (v1.2) designates PP4 as not applicable. |
cspec
|
| PP5 | N/A | Not applicable: the PALB2 expert panel specification (v1.2) designates PP5 as not applicable. |
cspec
clinvar
|
| BA1 | Not met | Not met: gnomAD v4.1 grpmax FAF 0.00255% is well below the >0.1% BA1 population-frequency threshold. |
cspec
gnomad_v4
|
| BS1 | Not met | Not met: gnomAD v4.1 grpmax FAF 0.00255% is below the >0.01% BS1 population-frequency threshold. |
cspec
gnomad_v4
|
| BS2 | Not assessed | Not assessed: no healthy adults with this genotype and adequate age context were documented; population databases cannot be used for BS2. |
cspec
gnomad_v4
|
| BS3 | N/A | Not applicable: the PALB2 expert panel specification (v1.2) designates BS3 as not applicable. |
cspec
PMID:25741868
|
| BS4 | Not assessed | Not assessed: no family data showing absence of segregation (LOD score or Bayes factor) were available. |
cspec
|
| BP1 | Met | Met (Supporting): BP1 applies to all missense variants under the PALB2 rules, and c.829G>A is missense (p.Asp277Asn). |
cspec
|
| BP2 | N/A | Not applicable: the PALB2 expert panel specification (v1.2) designates BP2 as not applicable. |
cspec
|
| BP3 | N/A | Not applicable: the PALB2 expert panel specification (v1.2) designates BP3 as not applicable. |
cspec
|
| BP4 | Met | Met (Supporting): SpliceAI max delta 0.002 meets the <=0.1 threshold, indicating no predicted splice impact. |
cspec
spliceai
revel
bayesdel
|
| BP5 | N/A | Not applicable: the PALB2 expert panel specification (v1.2) designates BP5 as not applicable. |
cspec
|
| BP6 | N/A | Not applicable: the PALB2 expert panel specification (v1.2) designates BP6 as not applicable. |
cspec
clinvar
|
| BP7 | N/A | Not applicable: BP7 requires a synonymous or deep-intronic variant, and this is a missense change. |
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.