PALB2c.2469C>GLikely benign

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Variant interpretation report

PALB2 c.2469C>G, p.(Leu823=)

NM_024675.4:c.2469C>G NP_078951.2:p.(Leu823=) View identifiers

Classification

Likely benign

Variant description:

No variant summary was recorded for this case.

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

Likely benign.A likely benign 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: 2 supporting (benign)
Expert rules: ClinGen PALB2 VCEP v1.2.0
Other laboratories (ClinVar): 9 Likely benign · 1 Benign · 1 likely benign
Pipeline record: 27 May 2026

Evidence considered

View criteria

Applied evidence criteria

BP4 (supporting): Computational splicing evidence supports no impact on splicing. SpliceAI predicts a maximum delta score of 0.00, which is below the PALB2 BP4 threshold of ≤0.1.
BP7 (supporting): This is a synonymous PALB2 variant, and available computational evidence does not suggest an RNA splice defect. SpliceAI predicts no significant splice impact, with a maximum delta score of 0.00.

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: 0 Benign evidence criteria: 2

Pathogenic criteria applied · 0

No pathogenic criterion marked as applied in the recorded assessment.

Benign criteria applied · 2

BP4Supporting

BP4 · supporting

Computational splicing evidence supports no impact on splicing. SpliceAI predicts a maximum delta score of 0.00, which is below the PALB2 BP4 threshold of ≤0.1.

BP7Supporting

BP7 · supporting

This is a synonymous PALB2 variant, and available computational evidence does not suggest an RNA splice defect. SpliceAI predicts no significant splice impact, with a maximum delta score of 0.00.

Recorded classification: Likely benign

Richards et.al., 2015 - Combining rules v1.2.0 criteria-combination framework: matched Rule19 (Benign.Supporting >=2) with applied criteria: BP7 supporting, BP4 supporting; maps to Likely Benign.

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

6 / 1,614,212 alleles

gnomAD v4.1: 6 / 1,614,212 alleles. Recorded AF 3.71698e-06. Recorded homozygote count 0.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

This variant is present in gnomAD-Canada v1.0 (AF= 0.000108601; MAF= 0.01086%, 2/18416 alleles, homozygotes = 0) and has highest observed frequency in the eas population (AF= 0.00149477; grpmax FAF95= 0.00026546).

No listed criterion applied

gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗

SpliceAI score

0.000 maximum delta

Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4, BP7 → SpliceAI ↗

ClinVar submissions

11 reported laboratory submissions

9 Likely benign · 1 Benign · 1 likely benign.

Context only ClinVar ↗

Functional evidence

Statement recorded

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

No listed criterion applied OncoKB ↗

COSMIC

Cancer Hotspots

Somatic evidence

No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

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 · 5 not met · 6 not assessed · 15 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.2469C>G (p.Leu823=) variant has been reported in ClinVar predominantly as likely benign or benign, and no expert panel submission was identified.

In gnomAD v4.1, this variant is present at 6/1,614,212 alleles overall (0.00037%) with a highest observed population frequency of 5/62,506 alleles (0.00800%) in Remaining individuals; it is absent from gnomAD v2.1.

This synonymous variant is predicted to have no meaningful effect on splicing, with a SpliceAI maximum delta score of 0.00; under the PALB2 specification, this supports BP4 and is consistent with BP7.

Met · 2

BP4 SupportingComputational splicing evidence supports no impact on splicing. SpliceAI predicts a maximum delta score of 0.00, which is below the PALB2 BP4 threshold of ≤0.1. Details ▾Hide ▴

Rule

Splicing: no predicted impact via splicing, SpliceAI ≤ 0.1

Evidence considered

SpliceAI max delta score 0.00

Sources

cspec ↗spliceai ↗

BP7 SupportingThis is a synonymous PALB2 variant, and available computational evidence does not suggest an RNA splice defect. SpliceAI predicts no significant splice impact, with a maximum delta score of 0.00. Details ▾Hide ▴

Rule

Use for synonymous variants; BP7(RNA) may be weighted when lack of aberrant RNA defect is observed

Evidence considered

Protein consequence p.(Leu823=)
SpliceAI max delta score 0.00

Sources

cspec ↗spliceai ↗

Not met · 5 · evaluated, threshold not reached

PVS1 This synonymous variant does not fall into the PALB2 PVS1 loss-of-function categories, and available splicing evidence does not indicate an abnormal splice effect. SpliceAI shows a maximum delta score of 0.00. Details ▾Hide ▴

Rule

Use PALB2 PVS1 decision tree

Evidence considered

Protein consequence p.(Leu823=)
Generic PVS1 scaffold classified variant bucket as other
SpliceAI max delta score 0.00

Sources

cspec ↗pvs1_gene_contextpvs1_variant_assessmentspliceai ↗

PM2 This variant is not rare enough for PM2_Supporting under the PALB2 specification. In gnomAD v4.1, the overall frequency is 0.00037% (6/1,614,212), which is above the ≤0.000333% threshold, and the highest observed population frequency is 0.00800% (5/62,506). Details ▾Hide ▴

Rule

Frequency ≤ 1/300,000 (0.000333%) in gnomAD v4 dataset for PM2_Supporting

Evidence considered

gnomAD v4.1 total AF 0.00037% (6/1614212)
gnomAD v4.1 best observed population AF 0.00800% (5/62506)

Sources

gnomad_v4 ↗cspec ↗

PP3 Computational evidence does not support a splice-altering effect. SpliceAI predicts a maximum delta score of 0.00, which is below the PALB2 PP3 threshold of ≥0.2. Details ▾Hide ▴

Rule

Splicing: predicted impact via splicing, SpliceAI ≥ 0.2

Evidence considered

SpliceAI max delta score 0.00
No REVEL or BayesDel score was available for this synonymous variant

Sources

cspec ↗spliceai ↗

BA1 Population frequency is far below the PALB2 BA1 threshold. In gnomAD v4.1, the highest observed population frequency is 0.00800% (5/62,506), which is below the >0.1% threshold. Details ▾Hide ▴

Rule

Grpmax filtering AF > 0.1% in gnomAD v4 dataset

Evidence considered

gnomAD v4.1 best observed population AF 0.00800% (5/62506)

Sources

gnomad_v4 ↗cspec ↗

BS1 Population frequency does not reach the PALB2 BS1 threshold. In gnomAD v4.1, the highest observed population frequency is 0.00800% (5/62,506), which is below the >0.01% threshold. Details ▾Hide ▴

Rule

Grpmax filtering AF > 0.01% in gnomAD v4 dataset

Evidence considered

gnomAD v4.1 best observed population AF 0.00800% (5/62506)

Sources

gnomad_v4 ↗cspec ↗

Not assessed · 6 · no assessment recorded

PS1 No PALB2 PS1 splicing comparator evidence was identified to show that this variant produces the same established pathogenic splice effect as a known pathogenic variant. Details ▾Hide ▴

Rule

Use PALB2 PS1 splicing table

Evidence considered

PALB2 PS1 requires use of the PALB2 PS1 splicing table
SpliceAI max delta score 0.00

Still missing

Variant-specific PALB2 PS1 splicing table comparison or RNA comparator evidence

Sources

cspec ↗spliceai ↗

PS4 No qualifying PALB2 case-control study showing a significant enrichment of this variant in affected individuals was identified. Details ▾Hide ▴

Rule

p-value ≤ 0.05 and odds ratio, hazard ratio, or relative risk ≥ 3 or lower 95% CI ≥ 1.5

Evidence considered

ClinVar observations do not establish PALB2 PS4 case-control evidence

Still missing

Variant-specific case-control data meeting PALB2 PS4 thresholds

Sources

cspec ↗clinvar ↗

PM3 No Fanconi anemia proband data or confirmed in trans occurrences with a pathogenic PALB2 variant were identified, so PM3 cannot be scored. Details ▾Hide ▴

Rule

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

Evidence considered

PALB2 PM3 uses a Fanconi-anemia-specific point system

Still missing

Recessive disease case data with phase information
PM3 point-based evidence

Remaining individuals5 / 62,506	8e-05
European (non-Finnish)1 / 1,180,042	8.5e-07

PALB2 c.2469C>G, p.(Leu823=)

Variant description:

In plain language

About PALB2

How it was classified

Recorded applied criteria

Evidence at a glance

Technical detail

Met · 2

Rule

Evidence considered

Sources

Rule

Evidence considered

Sources

Not met · 5 · evaluated, threshold not reached

Rule

Evidence considered

Sources

Rule

Evidence considered

Sources

Rule

Evidence considered

Sources

Rule

Evidence considered

Sources

Rule

Evidence considered

Sources

Not assessed · 6 · no assessment recorded

Rule

Evidence considered

Still missing

Sources

Rule

Evidence considered

Still missing

Sources

Rule

Evidence considered

Still missing

Sources

Rule

Evidence considered

Still missing

Sources

Rule

Evidence considered

Still missing

Sources

Rule

Evidence considered

Still missing

Sources

Evidence considered

Sources

Evidence considered

Sources

VCEP rule

Evidence considered

Sources

VCEP rule

Evidence considered

Sources

Rule

Evidence considered

Sources

VCEP rule

Evidence considered

Sources

VCEP rule

Evidence considered

Sources

VCEP rule

Evidence considered

Sources

Evidence considered

Sources