LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Variant classification summary
NM_024675.4:c.3113G>A
PALB2
· NP_078951.2:p.(Trp1038Ter)
· NM_024675.4
GRCh37: chr16:23632683 C>T
·
GRCh38: chr16:23621362 C>T
Gene:
PALB2
Transcript:
NM_024675.4
Final call
VUS
PVS1 very strong
PS4 strong
PM5 supporting
PP5 supporting
BS1 strong
Variant details
Gene
PALB2
Transcript
NM_024675.4
Protein
NP_078951.2:p.(Trp1038Ter)
gnomAD AF
0.0002083848056281367 (v4.1)
ClinVar
Pathogenic
OncoKB
Likely Oncogenic
Classification rationale
Interpretation summary
Generated evidence synthesis
1
PVS1 (very strong): p.Trp1038Ter is an upstream truncation, and exon 10 skipping affects PALB2’s indispensable WD40 domain.
2
PS4 (strong): exact-variant case-control data report HR 30.1, 95% CI 7.5–120, and P<0.0001.
3
PM5 (supporting): the truncating variant lies upstream of the VCEP p.His1184 cutoff.
4
PP5 (supporting): the ClinVar expert panel classified the variant as Pathogenic.
5
BS1 (strong): gnomAD v4.1 grpmax filtering allele frequency is 0.025238%, above the VCEP threshold.
Final determination:
Under the PALB2 VCEP Version 1.3 framework, PVS1 very strong plus PS4 strong satisfy Rule1 for Pathogenic while BS1 strong satisfies Rule20 for Likely Benign; contradictory satisfied rules yield 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 | Met | Met, very strong: p.Trp1038Ter is upstream of c.3301 and exon 10 skipping removes sequence from PALB2's indispensable WD40 domain. |
cspec
vcep_palb2_pvs1_v1_3
PMID:23448497
|
| PS1 | N/A | Not applicable: PALB2 PS1 is restricted to comparable splice defects, whereas c.3113G>A produces the nonsense variant p.Trp1038Ter. |
vcep_palb2_ps1_1_3
cspec
|
| PS2 | N/A | Not applicable: the PALB2 VCEP states that informative de novo occurrences have not been observed for autosomal-dominant disease. |
cspec
|
| PS3 | N/A | Not applicable: the PALB2 VCEP Version 1.3 explicitly marks PS3 as "Not applicable". |
cspec
|
| PS4 | Met | Met, Strong: exact-variant case-control data reported HR 30.1, 95% CI 7.5–120, and P<0.0001, satisfying the VCEP PS4 thresholds. |
cspec
PMID:21182766
PMID:28779002
PMID:23448497
PMID:18053174
|
| PM1 | N/A | Not applicable: the PALB2 VCEP excludes PM1 because missense pathogenic variation is not yet a confirmed disease mechanism. |
cspec
|
| PM2 | Not met | Not met: the highest gnomAD v4.1 subpopulation AF is 0.027778%, above the PALB2 VCEP PM2 threshold of ≤0.000333%. |
cspec
gnomad_v4
gnomad_v2
|
| PM3 | Not assessed | Not assessed: no Fanconi Anemia PM3-table entry or documented pathogenic variant in trans is available to establish a VCEP PM3 point total. |
cspec
vcep_palb2_pm3_bs2_1_3
|
| PM4 | N/A | Not applicable: the VCEP restricts PM4 to stop-loss variants, whereas c.3113G>A is a stop-gain nonsense variant. |
cspec
|
| PM5 | Met | Met, Supporting: p.Trp1038Ter is an NMD-prone truncation upstream of p.His1184, satisfying the PALB2 VCEP PM5_Supporting rule. |
cspec
vcep_palb2_pvs1_v1_3
|
| PM6 | N/A | Not applicable: the PALB2 VCEP says informative de novo occurrences have not been observed for PALB2 autosomal-dominant or autosomal-recessive disease. |
cspec
|
| PP1 | Not assessed | Not assessed: segregation occurred in two families, but no quantitative LOD or Bayes factor is available to meet the VCEP's PP1 thresholds. |
cspec
PMID:21182766
|
| PP2 | N/A | Not applicable: PALB2 PP2 is prohibited by the VCEP and the variant is nonsense, not missense. |
cspec
|
| PP3 | N/A | Not applicable: the PALB2 VCEP PP3 splicing rule covers silent, missense/in-frame, and specified intronic variants, not nonsense variants. |
cspec
|
| PP4 | N/A | Not applicable: the PALB2 VCEP excludes PP4 for hereditary breast cancer because genetic heterogeneity prevents specific phenotype discrimination. |
cspec
|
| PP5 | Met | Not applicable: the PALB2 VCEP explicitly prohibits use of PP5 for this VCEP. |
cspec
clinvar
|
| BA1 | Not met | Not met: gnomAD v4.1 grpmax FAF is 0.025238%, below the PALB2 VCEP BA1 threshold of >0.1%. |
cspec
gnomad_v4
gnomad_v2
|
| BS1 | Met | Met at strong: gnomAD v4.1 grpmax FAF is 0.025238%, exceeding the PALB2 VCEP BS1 threshold of >0.01%. |
cspec
gnomad_v4
|
| BS2 | Not assessed | Not assessed: the governing BS2 table has no c.3113G>A/p.Trp1038Ter/p.W1038* row, and available controls are from a prohibited population-based cohort. |
cspec
vcep_palb2_pm3_bs2_1_3
PMID:21182766
|
| BS3 | N/A | Not applicable: the PALB2 VCEP Version 1.3 explicitly marks BS3 as "Not applicable". |
cspec
|
| BS4 | Not assessed | Not assessed: no non-segregation LOD or Bayes factor is available to meet the VCEP's BS4 thresholds. |
cspec
PMID:21182766
|
| BP1 | N/A | Not applicable: BP1 applies to missense variants, but c.3113G>A produces the nonsense variant p.Trp1038Ter. |
cspec
|
| BP2 | N/A | Not applicable: the PALB2 VCEP CSPEC entry explicitly marks BP2 as Not Applicable. |
cspec
|
| BP3 | N/A | Not applicable: the VCEP excludes BP3 because PALB2 lacks repetitive regions without known function, and this variant is a nonsense stop-gain. |
cspec
|
| BP4 | N/A | Not applicable: BP4 no-impact splicing evidence cannot negate this variant's VCEP-recognized nonsense truncation. |
cspec
|
| BP5 | N/A | Not applicable: the PALB2 VCEP prohibits BP5 because co-occurring pathogenic variants are expected and may not alter phenotype. |
cspec
|
| BP6 | N/A | Not applicable: the PALB2 VCEP explicitly prohibits use of BP6 for this VCEP. |
cspec
|
| BP7 | N/A | Not applicable: BP7 is restricted to synonymous or deep intronic variants, whereas this variant is a nonsense substitution. |
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.