PALB2c.3512delLikely pathogenic

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Variant interpretation report

PALB2 c.3512del, p.(Leu1171CysfsTer20)

NM_024675.3:c.3512del NP_078951.2:p.(Leu1171CysfsTer20) View identifiers

Classification

Likely pathogenic

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.

Likely pathogenic.A likely pathogenic classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About PALB2

No gene-level summary was recorded for this case.

Key facts

Evidence used: 1 very strong (pathogenic) · 1 supporting (pathogenic)
Expert rules: ClinGen PALB2 VCEP v1.2.0

Evidence considered

View criteria

Applied evidence criteria

PVS1 (very strong): This variant is a frameshift in PALB2, a gene in which loss of function is an established disease mechanism. Although the altered transcript is expected to escape nonsense-mediated decay because the change is in the terminal coding exon, the PALB2 specification states that variants escaping nonsense-mediated decay but disrupting the indispensable C-terminal WD40 domain can still be granted full PVS1; this frameshift alters the WD40 tail and replaces the clinically relevant terminal residues.
PM2 (supporting): This variant is absent from gnomAD v4.1, which is below the PALB2 PM2_Supporting threshold of ≤0.000333%. It is also absent from gnomAD v2.1, supporting rarity in population databases.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

01The reasoning

How it was classified

The recorded framework is ClinGen PALB2 VCEP v1.2.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 2 Benign evidence criteria: 0

Pathogenic criteria applied · 2

PVS1Very strong

PVS1 · very strong

This variant is a frameshift in PALB2, a gene in which loss of function is an established disease mechanism. Although the altered transcript is expected to escape nonsense-mediated decay because the change is in the terminal coding exon, the PALB2 specification states that variants escaping nonsense-mediated decay but disrupting the indispensable C-terminal WD40 domain can still be granted full PVS1; this frameshift alters the WD40 tail and replaces the clinically relevant terminal residues.

PM2Supporting

PM2 · supporting

This variant is absent from gnomAD v4.1, which is below the PALB2 PM2_Supporting threshold of ≤0.000333%. It is also absent from gnomAD v2.1, supporting rarity in population databases.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Likely pathogenic

Richards et.al., 2015 - Combining rules v1.2.0 criteria-combination framework: matched Rule19 (1 Pathogenic.Very Strong + 1 Pathogenic.Supporting) with applied criteria: PVS1 very strong, PM2 supporting; maps to Likely Pathogenic.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

gnomAD v4.1

gnomAD v2.1

Population frequency

Not recorded

gnomAD v4.1 allele counts were not recorded for this variant.

gnomAD v2.1

Absent from gnomAD v2.1.

Applied · PM2 →

gnomAD v4.1 ↗gnomAD v2.1 ↗

No screenshot for this evidence

Computational predictions

Not recorded

No SpliceAI or REVEL score is recorded in the fields used for this tile.

No listed criterion applied

ClinVar submissions

Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗

Functional evidence

Statement recorded

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

No listed criterion applied OncoKB ↗

COSMIC

Cancer Hotspots

Somatic evidence

Not assessed

No COSMIC evidence statement is recorded in this case.

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only

COSMIC ↗Cancer Hotspots ↗

For specialists

Technical detail

ACMG/AMP criteria under ClinGen PALB2 VCEP v1.2.0, with the data and sources behind each one.

28 criteria with recorded statuses: 2 met · 6 not met · 4 not assessed · 16 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5

Benign

BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7

Met Not met Not assessed Not applicable

The PALB2 c.3512del (p.(Leu1171CysfsTer20), p.(L1171Cfs*20)) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar as uncertain significance by the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel.

This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the PALB2 PM2_Supporting threshold of 0.000333% and does not meet the BA1 (>0.1%) or BS1 (>0.01%) population thresholds.

PALB2 loss of function is an established disease mechanism, and the PALB2 specification states that variants predicted to escape nonsense-mediated decay but disrupting the indispensable C-terminal WD40 domain can still receive full PVS1; this terminal frameshift alters that WD40 tail.

SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.01, which is below the PALB2 PP3 threshold of 0.2 and within the BP4 splice threshold of 0.1, although that splice prediction does not remove concern for the protein-disrupting frameshift effect.

Met · 2

PVS1 Very strongThis variant is a frameshift in PALB2, a gene in which loss of function is an established disease mechanism. Although the altered transcript is expected to escape nonsense-mediated decay because the change is in the terminal coding exon, the PALB2 specification states that variants escaping nonsense-mediated decay but disrupting the indispensable C-terminal WD40 domain can still be granted full PVS1; this frameshift alters the WD40 tail and replaces the clinically relevant terminal residues. Details ▾Hide ▴

Rule

Use PALB2 PVS1 Decision Tree

Evidence considered

PALB2-specific guidance allows full PVS1 for variants predicted to escape NMD when the WD40 domain is adversely affected.
The variant is a frameshift affecting the extreme C terminus of PALB2.

Still missing

The PALB2 exon-map decision tree itself was not separately retrieved as a local file.
Because this is a terminal frameshift with a prior expert-panel VUS in ClinVar
manual review of the exact PALB2 PVS1 decision tree remains appropriate.

Sources

cspec ↗pvs1_gene_contextpvs1_variant_assessment

PM2 SupportingThis variant is absent from gnomAD v4.1, which is below the PALB2 PM2_Supporting threshold of ≤0.000333%. It is also absent from gnomAD v2.1, supporting rarity in population databases. Details ▾Hide ▴

Rule

Frequency ≤ 1/300,000 (0.000333%) in gnomAD v4 dataset

Evidence considered

Absent from gnomAD v4.1.
Absent from gnomAD v2.1.

Sources

gnomad_v4 ↗gnomad_v2 ↗cspec ↗

Not met · 6 · evaluated, threshold not reached

PS4 Published data support PALB2 truncating variants as a risk class, but no case-control study or exact-variant enrichment data were identified for c.3512del that meet the PALB2 PS4 threshold of p-value ≤0.05 with odds ratio, hazard ratio, or relative risk ≥3 or lower 95% confidence interval ≥1.5. Details ▾Hide ▴

Rule

Case-control studies; p-value ≤0.05 AND (Odds ratio, hazard ratio, or relative risk ≥3 OR lower 95% CI ≥1.5).

Evidence considered

Gene-level case-control evidence exists for PALB2 truncating variants.
No exact-variant prevalence comparison was identified for c.3512del.

Still missing

No exact-variant case-control dataset was identified.
No public count of unrelated probands with this specific variant was identified.

Sources

cspec ↗PMID:28779002 ↗clinvar ↗

PM5 The PALB2 specification applies PM5_Supporting to frameshifting or truncating variants with premature termination codons upstream of p.Tyr1183. This frameshift changes the terminal coding sequence and extends beyond the normal stop rather than creating a premature stop upstream of p.Tyr1183, so the PM5 rule is not met. Details ▾Hide ▴

Rule

Apply to frameshifting or truncating variants with premature termination codons upstream of p.Tyr1183.

Evidence considered

PALB2 PM5 is limited to truncating variants with a premature stop upstream of p.Tyr1183.
This variant is p.(Leu1171CysfsTer20) / p.(L1171Cfs*20).

Still missing

Terminal-protein modeling could further clarify the exact structural consequence
but it does not change that the stated PALB2 PM5 threshold is not met.

Sources

cspec ↗pvs1_variant_assessment

PP3 SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.01. This is below the PALB2 PP3 splice threshold of ≥0.2, so PP3 is not met. Details ▾Hide ▴

Rule

Splicing: Predicted impact via splicing (SpliceAI ≥0.2)

Evidence considered

SpliceAI max delta score = 0.01.

Sources

spliceai ↗cspec ↗

BA1 This variant is absent from gnomAD v4.1 and therefore does not meet the PALB2 BA1 threshold of group maximum filtering allele frequency >0.1%. Details ▾Hide ▴

Rule

Grpmax Filtering AF >0.1% in gnomAD v4 dataset

Evidence considered

Absent from gnomAD v4.1.

Sources

gnomad_v4 ↗cspec ↗

BS1 This variant is absent from gnomAD v4.1 and therefore does not meet the PALB2 BS1 threshold of group maximum filtering allele frequency >0.01%. Details ▾Hide ▴

Rule

Grpmax Filtering AF >0.01% in gnomAD v4 dataset

Evidence considered

Absent from gnomAD v4.1.

Sources

gnomad_v4 ↗cspec ↗

BP4 SpliceAI predicts no significant splice impact, with a maximum delta score of 0.01, which is within the PALB2 BP4 splice threshold of ≤0.1. However, this prediction addresses splicing only and does not indicate no impact on the gene product because the variant remains a protein-altering frameshift, so BP4 was not applied. Details ▾Hide ▴

Rule

Splicing: No predicted impact via splicing (SpliceAI ≤0.1). Do not apply for missense variants.

Evidence considered

SpliceAI max delta score = 0.01.
The variant is still a terminal frameshift affecting the protein sequence.

Sources

spliceai ↗cspec ↗

Not assessed · 4 · no assessment recorded

PM3 No evidence was identified that this variant has been observed in trans with another pathogenic PALB2 variant in an individual with Fanconi anemia, so PM3 could not be evaluated. Details ▾Hide ▴

Rule

PM3 = 2 points; PM3_Supporting = 1 point; PM3_Strong ≥ 4 points; PM3_VeryStrong ≥ 8 points

Evidence considered

PM3 in PALB2 requires Fanconi anemia point-based evidence.

Still missing

No phase-confirmed biallelic PALB2 observations were identified.
No Fanconi anemia case-level data for this variant were identified.