Classification rationale

PM2 BP4BP6BP7 Likely Benign

PALB2 c.135G>A

The PALB2 c.135G>A (p.Lys45=) variant has been reported in ClinVar with an expert panel classification of likely benign.¹ This variant is present in gnomAD v4.1 at 2/1,614,022 alleles (AF 0.00012%) with a highest observed population frequency of 0.00017% and grpmax FAF 2.8e-07, which is below the PALB2 PM2_Supporting threshold of 0.000333% and below the BS1 and BA1 benign frequency thresholds.² SpliceAI predicts no significant splice impact for this synonymous variant, with a maximum delta score of 0.00, which supports BP4 and argues against PP3 or a splice-based loss-of-function interpretation.³

PM2 + BP4 + BP6 + BP7 → Likely Benign

1 clinvar ↗

2 gnomad_v4 ↗cspec ↗

3 spliceai ↗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_024675.3 · variants mapped to exon structure

PALB2 NM_024675.3

Fetching transcript structure from UCSC…

Applied criteria · 4 applied · 10 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 · 4

Strength Supporting Moderate Strong Very strong

PM2 supporting Pathogenic

This variant is present in gnomAD v4.1 at 2/1,614,022 alleles (AF 0.00012%), which is below the PALB2 PM2_Supporting threshold of 0.000333%. This supports PM2 at supporting strength.

PALB2 PM2_Supporting threshold ≤0.000333% in gnomAD v4gnomAD v4.1 total AF 1.23914e-06 (0.00012%)

cspec ↗gnomad_v4 ↗

BP4 supporting Benign

SpliceAI predicts no significant splice impact for this variant, with a max delta score of 0.00, which is below the PALB2 BP4 threshold of 0.1. This supports BP4 at supporting strength.

PALB2 BP4 splicing threshold ≤0.1SpliceAI max delta score 0.00

cspec ↗spliceai ↗

BP6 supporting Benign

Expert panel ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen classified as Likely benign.

PALB2 VCEP marks BP6 not applicableClinVar expert panel classification

cspec ↗clinvar ↗

BP7 supporting Benign

This synonymous PALB2 variant has no predicted splice effect, with SpliceAI max delta score 0.00. Under the PALB2 specification, this supports BP7 at supporting strength.

PALB2 BP7 applies to synonymous variantsSpliceAI max delta score 0.00

cspec ↗spliceai ↗

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

Pathogenic

PVS1 This synonymous variant does not fall within the PALB2 loss-of-function variant categories used for PVS1, and available splicing evidence does not support a loss-of-function effect.

PS1 No evidence was identified showing that this variant has the same established pathogenic splicing effect as a previously classified pathogenic PALB2 variant, so PS1 was not assessed.

PS4 This variant has been reported in ClinVar, but no case-control study or statistically significant enrichment in affected individuals was identified.

PM3 No evidence was identified that this variant was observed in trans with a pathogenic PALB2 variant in an individual with Fanconi anemia, so PM3 was not assessed.

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

PP3 SpliceAI predicts no significant splice impact for this synonymous variant (max delta score 0.00), which is below the PALB2 PP3 threshold of 0.2.

Benign

BA1 The gnomAD v4.1 filtering allele frequency is far below the PALB2 BA1 threshold of greater than 0.1%.

BS1 The gnomAD v4.1 frequency is below the PALB2 BS1 threshold of greater than 0.01%.

BS2 No evidence was identified showing this variant in the number of unaffected individuals required by the PALB2 Fanconi anemia BS2 framework, so BS2 was not assessed.

BS4 No non-segregation data were identified for this variant, so BS4 was not assessed.

N/A · 14 PS2 · PS3 · PM1 · PM4 · PM5 · PM6 · PP2 · PP4 · PP5 · BS3 · BP1 · BP2 · BP3 · BP5

Research & evidence

Population frequency · supports benign

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 1.23914e-06; MAF= 0.00012%, 2/1614022 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.69495e-06; MAF= 0.00017%, 2/1179974 alleles, homozygotes = 0); grpmax FAF= 2.8e-07.

v2.1

This variant is present in gnomAD v2.1 (AF= 3.97674e-06; MAF= 0.00040%, 1/251462 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.7909e-06; MAF= 0.00088%, 1/113754 alleles, homozygotes = 0).

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.00012% · 2 / 1,614,022
0 hom · FAF 2.8e-05%

European (non-Finnish)

2 / 1,179,974

0.00017%

+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)

gnomAD v2.1

0.0004% · 1 / 251,462
0 hom

European (non-Finnish)

1 / 113,754

0.00088%

+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Likely benign (3 clinical laboratories) and as Benign (1 clinical laboratory) and as Likely Benign 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 = 0.00).

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

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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