Final classification

Uncertain Significance - Conflicting Evidence

PM2BP1

PALB2

c.2831T>A

p.Ile944Asn

This variant

The PALB2 c.2831T>A (p.Ile944Asn) variant has been reported in ClinVar and is currently classified there as uncertain significance, including an expert-panel ClinGen submission.

Transcript

NM_024675.3

HGVS · transcript:coding

NM_024675.3:c.2831T>A

GRCh38

chr16:23624012 A>T

GRCh37

chr16:23635333 A>T

Richards et.al., 2015 - Combining rules v1.2.0 criteria-combination framework: matched Rule31 (Benign.Supporting >=1 + Pathogenic.Supporting >=1) with applied criteria: BP1 supporting, PM2 supporting; maps to Uncertain Significance - Conflicting Evidence.

Classification rationale

PM2 BP1 Uncertain Significance - Conflicting Evidence

PALB2 c.2831T>A

The PALB2 c.2831T>A (p.Ile944Asn) variant has been reported in ClinVar and is currently classified there as uncertain significance, including an expert-panel ClinGen submission.¹ This variant is absent from gnomAD v2.1 and is present in gnomAD v4.1 at 3/1,577,962 alleles (0.00019%), which is below the PALB2 PM2_Supporting threshold of 0.000333%.² No variant-specific reviewed functional evidence was identified in the retrieved materials, and the PALB2 expert specification does not apply PS3 or BS3 in this framework.³ SpliceAI predicts no significant splice impact for this variant with a maximum delta score of 0.01; REVEL was 0.449 and BayesDel was -0.120213, but the PALB2 expert specification does not apply PP3 or BP4 to missense variants.⁴

PM2 + BP1 → Uncertain Significance - Conflicting Evidence

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗cspec ↗

3 oncokb ↗cspec ↗

4 spliceai ↗revelbayesdelcspec ↗

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_024675.3 · variants mapped to exon structure

PALB2 NM_024675.3

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 8 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 v2.1 and is present in gnomAD v4.1 at 3/1,577,962 alleles (0.00019%), which is below the PALB2 PM2 threshold of <=0.000333%. This supports rarity in the general population.

Absent from gnomAD v2.1gnomAD v4.1 AF 0.00019% (3/1577962)below PALB2 PM2 threshold 0.000333%.

gnomad_v2 ↗gnomad_v4 ↗cspec ↗

BP1 supporting review Benign

This variant is a missense substitution, and the PALB2 expert specification applies BP1 to all missense variants.

NM_024675.3:c.2831T>A predicts p.(Ile944Asn)a missense changePALB2 CSPEC applies BP1 to all missense variants.

cspec ↗

Assessed · not applied · 3 not met · 5 not assessed

Pathogenic

PVS1 Loss of function is an established PALB2 disease mechanism, but this variant is a missense substitution rather than a nonsense, frameshift, or canonical +/-1,2 splice variant.

PS4 This variant has been reported in ClinVar, including an expert-panel submission, but no case-control study, odds ratio, or other quantified enrichment data specific to this variant were identified to support PS4.

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

PP1 No segregation data were identified for this variant, so PP1 could not be assessed.

Benign

BA1 This variant is present in gnomAD v4.1 at 3/1,577,962 alleles (0.00019%), with a highest observed population frequency of 0.00111% in South Asian individuals, which is below the PALB2 BA1 threshold of >0.1%.

BS1 This variant is present in gnomAD v4.1 at 3/1,577,962 alleles (0.00019%), with a highest observed population frequency of 0.00111% in South Asian individuals, which is below the PALB2 BS1 threshold of >0.01%.

BS2 No data were identified showing the number of unaffected individuals or point-based evidence required to apply BS2 for PALB2-related Fanconi anemia.

BS4 No non-segregation data, LOD score, or Bayes factor were identified for this variant, so BS4 could not be assessed.

N/A · 18 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

This variant is present in gnomAD v4.1 (AF= 1.90119e-06; MAF= 0.00019%, 3/1577962 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 1.10762e-05; MAF= 0.00111%, 1/90284 alleles, homozygotes = 0); grpmax FAF= 2.9e-07.

v2.1

Absent from gnomAD v2.1.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.00019% · 3 / 1,577,962
0 hom · FAF 2.9e-05%

South Asian 1 / 90,284	0.0011%
European (non-Finnish) 2 / 1,147,306	0.00017%

+ 8 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American)

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 (2 clinical laboratories) and as Uncertain Significance by ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen (expert panel).

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.449. BayesDel score = -0.120213.

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. 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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