Classification rationale

PM2 BP1 Uncertain Significance - Conflicting Evidence

PALB2 c.968C>T

The PALB2 c.968C>T (p.Ala323Val) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar as a variant of uncertain significance.¹ This variant is absent from gnomAD v2.1 and gnomAD v4.1, so its population frequency is below the PALB2 PM2_Supporting threshold of 0.000333%.² SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.03, which is below the PALB2 PP3 splice threshold of 0.2.³ As a missense variant in PALB2, this change meets BP1 because pathogenic missense variation is considered uncommon in this gene under the PALB2 specifications.⁴

PM2 + BP1 → Uncertain Significance - Conflicting Evidence

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗cspec ↗

3 spliceai ↗cspec ↗

4 cspec ↗

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 · 12 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 Pathogenic

This variant is absent from gnomAD v4.1 and gnomAD v2.1. The observed population frequency is therefore 0, which is below the PALB2 PM2_Supporting threshold of ≤1/300,000 (0.000333%), so PM2_Supporting is met.

Absent from gnomAD v4.1Absent from gnomAD v2.1PALB2 PM2 is applied only at Supporting strength

cspec ↗gnomad_v4 ↗gnomad_v2 ↗

BP1 supporting Benign

This variant is a missense substitution, and PALB2 specifications apply BP1 to all missense variants because pathogenic missense variation is considered very uncommon in this gene. Therefore BP1 is met at Supporting strength.

Variant is missense p.(Ala323Val)PALB2 BP1 applies to all missense variants

cspec ↗

Assessed · not applied · 7 not met · 5 not assessed

Pathogenic

PVS1 This missense variant does not fall into the PALB2 loss-of-function PVS1 categories, and the generic PVS1 scaffold states that it is not a nonsense, frameshift, or canonical ±1,2 splice variant.

PS1 Available evidence does not support PS1.

PS4 This variant has been reported in ClinVar as uncertain significance, but no case-control study was identified showing a significant enrichment in affected individuals with p-value ≤0.05 and odds ratio, hazard ratio, or relative risk ≥3 or lower 95% confidence interval ≥1.5.

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

PM5 Available evidence does not support PM5.

PP1 No quantitative segregation data were identified for this variant, so the PALB2 LOD-score or Bayes factor thresholds for PP1 cannot be evaluated.

PP3 Available evidence does not support PP3.

Benign

BA1 This variant is absent from gnomAD v4.1, so the observed population frequency is 0, which is below the PALB2 BA1 threshold of >0.1%.

BS1 This variant is absent from gnomAD v4.1, so the observed population frequency is 0, which is below the PALB2 BS1 threshold of >0.01%.

BS2 No data were identified showing this variant in healthy individuals meeting the PALB2 Fanconi anemia BS2 point-based framework, so BS2 cannot be assessed.

BS4 No quantitative non-segregation data were identified for this variant, so the PALB2 BS4 LOD-score or Bayes factor thresholds cannot be evaluated.

BP4 SpliceAI predicts no significant splice impact with a maximum delta score of 0.03, which is at or below the PALB2 BP4 splice threshold of ≤0.1.

N/A · 14 PS2 · PS3 · PM1 · PM4 · PM6 · PP2 · PP4 · PP5 · BS3 · BP2 · BP3 · 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 (6 clinical laboratories).

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.061. BayesDel score = -0.514065.

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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