Classification rationale

PM2 BP1 Uncertain Significance - Conflicting Evidence

PALB2 c.1058A>T

The PALB2 c.1058A>T (p.Lys353Ile) variant has been reported in ClinVar as uncertain significance by a single submitter.¹ This variant is absent from gnomAD v2.1 and gnomAD v4.1, and its gnomAD v4.1 allele frequency is therefore below the PALB2 PM2_Supporting threshold of 0.000333%.² PALB2-specific rules support BP1 for this missense variant, while SpliceAI predicts no significant splice impact with a maximum delta score of 0.00 and PVS1, PP3, and BP4 are not applied in this missense setting.³

PM2 + BP1 → Uncertain Significance - Conflicting Evidence

1 clinvar ↗

2 cspec ↗gnomad_v2 ↗gnomad_v4 ↗

3 cspec ↗pvs1_variant_assessmentspliceai ↗

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.

Gene diagram · NM_024675.4 · variants mapped to exon structure

PALB2 NM_024675.4

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 7 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 2

Strength Supporting Moderate Strong Very strong

PM2 supporting review Pathogenic

This variant is absent from gnomAD v4.1 and gnomAD v2.1. The observed gnomAD v4.1 allele frequency is 0%, which is below the PALB2 PM2_Supporting threshold of ≤0.000333%, so PM2_Supporting is met.

gnomAD v4.1: absentgnomAD v2.1: absentPALB2 PM2_Supporting threshold: frequency ≤1/300

cspec ↗gnomad_v4 ↗gnomad_v2 ↗

BP1 supporting review Benign

This variant is a missense substitution, and the PALB2 VCEP applies BP1 to all missense variants because truncating variants are the predominant established disease mechanism for this gene.

NM_024675.4:c.1058A>T causes p.(Lys353Ile)a missense changePALB2 VCEP BP1 rule: apply to all missense variants

cspec ↗

Assessed · not applied · 2 not met · 5 not assessed

Pathogenic

PS4 This variant has been reported in ClinVar as uncertain significance by a single submitter, but no case-control study data, odds ratio, relative risk, or qualifying statistical enrichment data were identified; PS4 cannot be assessed.

PM3 No data were identified showing this variant in trans with a pathogenic PALB2 variant in an affected individual with Fanconi anemia, so PM3 cannot be assessed.

PP1 No family segregation data or quantitative LOD/Bayes factor evidence were identified to show co-segregation with disease, so PP1 cannot be assessed.

Benign

BA1 This variant is absent from gnomAD v4.1, so the observed allele frequency is 0%, which is below the PALB2 BA1 threshold of >0.1%; BA1 is not met.

BS1 This variant is absent from gnomAD v4.1, so the observed allele frequency is 0%, which is below the PALB2 BS1 threshold of >0.01%; BS1 is not met.

BS2 No data were identified showing this variant in unaffected individuals under the PALB2 BS2 point-based framework, so BS2 cannot be assessed.

BS4 No segregation study data or quantitative LOD/Bayes factor evidence were identified to show lack of segregation with disease, so BS4 cannot be assessed.

N/A · 19 PVS1 · PS1 · PS2 · PS3 · PM1 · PM4 · PM5 · PM6 · PP2 · PP3 · PP4 · PP5 · BS3 · BP2 · BP3 · BP4 · BP5 · BP6 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

Absent from gnomAD v4.1.

v2.1

Absent from gnomAD v2.1.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory).

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.086. BayesDel score = -0.4788.

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB has not reviewed this specific variant; no variant-level oncogenicity or biological effect is available. Gene-level context: PALB2, a scaffolding protein involved in DNA repair, is altered in various cancers.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots

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