Starting

Initialising…

PALB2

Final classification

Uncertain Significance - Conflicting Evidence

PALB2 c.2831T>A · p.Ile944Asn

PALB2

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.

Gene

PALB2

Transcript

NM_024675.3

HGVS · transcript:coding

NM_024675.3:c.2831T>A

Consequence

N/A

GRCh38

chr16:23624012 A>T

GRCh37

chr16:23635333 A>T

Basis 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. ▾

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 ↗

Gene diagram · NM_024675.3 · variants mapped to exon structure

PALB2 NM_024675.3

Fetching transcript structure from UCSC…

Applied criteria · 2 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

Benign evidence

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

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