Classification rationale

BS1BP4BP6BP7 Likely Benign

PALB2 c.1794G>A

The PALB2 c.1794G>A (p.Leu598=) variant has been reported in ClinVar with an expert panel Likely Benign classification and additional benign or likely benign clinical laboratory submissions.¹ In gnomAD v4.1, this variant is present at 47/1614132 alleles (0.00291%) with a grpmax filtering allele frequency of 0.04713%, which is above the PALB2 BS1 threshold of 0.01%; gnomAD v2.1 also shows the variant in population databases, including African/African American individuals.² SpliceAI predicts no significant splice impact for this synonymous variant, with a maximum delta score of 0.06, which is below the PALB2 BP4 threshold of 0.1 and below the PP3 threshold of 0.2.³

BS1 + BP4 + BP6 + BP7 → Likely Benign

1 clinvar ↗cspec ↗

2 gnomad_v4 ↗gnomad_v2 ↗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

BS1 strong Benign

This variant exceeds the PALB2 BS1 threshold in gnomAD v4.1. The grpmax filtering allele frequency is 0.04713%, which is above the BS1 threshold of 0.01%, supporting BS1 at strong strength.

gnomAD v4.1 grpmax FAF is 0.00047131 (0.04713%).The highest observed population frequency in gnomAD v4.1 is 46/75050 alleles in African/African American individuals (0.06129%)with 0 homozygotes.

gnomad_v4 ↗gnomad_v2 ↗cspec ↗

BP4 supporting Benign

Computational splicing evidence supports no effect on splicing. SpliceAI predicts a maximum delta score of 0.06, which is below the PALB2 BP4 threshold of 0.1, so BP4 is met at supporting strength.

SpliceAI scores are DS_AG 0.06DS_AL 0.01DS_DG 0.00

spliceai ↗cspec ↗

BP6 supporting Benign

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

PALB2 CSPEC marks BP6 as not applicable for this VCEP.ClinVar expert panel classification

cspec ↗clinvar ↗

BP7 supporting Benign

This is a synonymous PALB2 variant, and available computational evidence predicts no meaningful splice effect. SpliceAI shows a maximum delta score of 0.06, which is consistent with no significant splice impact, so BP7 is met at supporting strength.

c.1794G>A results in p.(Leu598=)a synonymous substitution.SpliceAI maximum delta score is 0.06.

cspec ↗spliceai ↗

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

Pathogenic

PVS1 This synonymous PALB2 variant does not fall into the default loss-of-function variant classes for PVS1, and available splicing evidence does not support a loss-of-function transcript.

PS1 Available evidence does not identify that this variant produces the same established pathogenic splicing effect as another PALB2 variant.

PS4 No case-control study, odds ratio, or quantified enrichment data were identified for this variant, so PS4 cannot be assessed from the available evidence.

PM2 This variant is present in gnomAD v4.1 at 47/1614132 alleles (0.00291%), which is above the PALB2 PM2_Supporting threshold of 1/300000 (0.000333%).

PM3 No data were identified showing this variant in trans with a pathogenic PALB2 variant in a proband meeting the Fanconi anemia scoring framework, so PM3 cannot be assessed.

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

PP3 Computational splicing evidence does not support a damaging effect.

Benign

BA1 The gnomAD v4.1 grpmax filtering allele frequency is 0.04713%, which is below the PALB2 BA1 threshold of 0.1%, so BA1 is not met.

BS2 No scored observations in unaffected individuals or other BS2 point-based evidence were identified, so BS2 cannot be assessed.

BS4 No non-segregation data were identified for this variant, so BS4 cannot be 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= 2.91178e-05; MAF= 0.00291%, 47/1614132 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000612925; MAF= 0.06129%, 46/75050 alleles, homozygotes = 0); grpmax FAF= 0.00047131.

v2.1

This variant is present in gnomAD v2.1 (AF= 7.07454e-05; MAF= 0.00707%, 20/282704 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000801218; MAF= 0.08012%, 20/24962 alleles, homozygotes = 0); grpmax FAF= 0.00056887.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.0029% · 47 / 1,614,132
0 hom · FAF 0.047%

African/African American 46 / 75,050	0.061%
Remaining individuals 1 / 62,504	0.0016%

+ 8 not observed (Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, European (non-Finnish))

gnomAD v2.1

0.0071% · 20 / 282,704
0 hom · FAF 0.057%

African/African American

20 / 24,962

0.08%

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

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Likely benign (7 clinical laboratories) and as Benign (3 clinical laboratories) 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 = 0.06).

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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