Starting

Initialising…

PALB2

Final classification

VUS

PALB2 c.154G>A · p.Val52Ile

PALB2

The PALB2 c.154G>A (p.Val52Ile) variant has been reported in ClinVar with conflicting single-submitter interpretations of uncertain significance and likely benign.

Gene

PALB2

Transcript

NM_024675.4

HGVS · transcript:coding

NM_024675.4:c.154G>A

Consequence

N/A

GRCh38

chr16:23637907 C>T

GRCh37

chr16:23649228 C>T

Basis Richards et.al., 2015 - Combining rules v1.2.0 criteria-combination framework was evaluated deterministically with applied criteria: BP1 supporting; no rule matched the adjudicated criteria. ▾

Richards et.al., 2015 - Combining rules v1.2.0 criteria-combination framework was evaluated deterministically with applied criteria: BP1 supporting; no rule matched the adjudicated criteria.

Classification rationale

BP1 VUS

PALB2 c.154G>A

The PALB2 c.154G>A (p.Val52Ile) variant has been reported in ClinVar with conflicting single-submitter interpretations of uncertain significance and likely benign.¹ This variant is absent from gnomAD v2.1 and is present at very low overall frequency in gnomAD v4.1 (3/1,614,050 alleles; 0.00019%), but the highest observed subpopulation frequency is 0.00160% (1/62,510 alleles), which is above the PALB2 PM2 threshold exception and remains below the BS1 and BA1 population thresholds.² SpliceAI predicts no significant splice impact (max delta score 0.01), and REVEL (0.045) and BayesDel (-0.518425) are low; however, the PALB2 VCEP does not use PP3 or BP4 for missense variants, while BP1 is applicable to all PALB2 missense variants.³

BP1 → VUS

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗cspec ↗

3 spliceai ↗revelbayesdelcspec ↗

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

PALB2 NM_024675.4

Fetching transcript structure from UCSC…

Applied criteria · 1 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= 1.85868e-06; MAF= 0.00019%, 3/1614050 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 1.59974e-05; MAF= 0.00160%, 1/62510 alleles, homozygotes = 0); grpmax FAF= 2.8e-07.

v2.1

Absent from gnomAD v2.1.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.00019% · 3 / 1,614,050
0 hom · FAF 2.8e-05%

Remaining individuals 1 / 62,510	0.0016%
European (non-Finnish) 2 / 1,179,990	0.00017%

+ 8 not observed (Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, 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 (1 clinical laboratory) and as Likely benign (1 clinical laboratory).

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.045. BayesDel score = -0.518425.

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