Starting

Initialising…

PALB2

Final classification

Uncertain Significance - Conflicting Evidence

PALB2 c.1058A>T · p.Lys353Ile

PALB2

The PALB2 c.1058A>T (p.Lys353Ile) variant has been reported in ClinVar as uncertain significance by a single submitter.

Gene

PALB2

Transcript

NM_024675.4

HGVS · transcript:coding

NM_024675.4:c.1058A>T

Consequence

N/A

GRCh38

chr16:23635488 T>A

GRCh37

chr16:23646809 T>A

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.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 ↗

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

PALB2 NM_024675.4

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

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