Classification rationale

BP7BP4 Likely Benign

PALB2 c.2469C>G

The PALB2 c.2469C>G (p.Leu823=) variant has been reported in ClinVar predominantly as likely benign or benign, and no expert panel submission was identified.¹ In gnomAD v4.1, this variant is present at 6/1,614,212 alleles overall (0.00037%) with a highest observed population frequency of 5/62,506 alleles (0.00800%) in Remaining individuals; it is absent from gnomAD v2.1.² This synonymous variant is predicted to have no meaningful effect on splicing, with a SpliceAI maximum delta score of 0.00; under the PALB2 specification, this supports BP4 and is consistent with BP7.³

BP7 + BP4 → Likely Benign

1 clinvar ↗

2 gnomad_v4 ↗gnomad_v2 ↗

3 spliceai ↗cspec ↗

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

PALB2 NM_024675.4

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 11 assessed

Applied · 2

Strength Supporting Moderate Strong Very strong

✓

BP4 supporting Benign

Computational splicing evidence supports no impact on splicing. SpliceAI predicts a maximum delta score of 0.00, which is below the PALB2 BP4 threshold of ≤0.1.

SpliceAI max delta score 0.00

cspec ↗spliceai ↗

✓

BP7 supporting Benign

This is a synonymous PALB2 variant, and available computational evidence does not suggest an RNA splice defect. SpliceAI predicts no significant splice impact, with a maximum delta score of 0.00.

Protein consequence p.(Leu823=)SpliceAI max delta score 0.00

cspec ↗spliceai ↗

Assessed · not applied

Pathogenic

PVS1 This synonymous variant does not fall into the PALB2 PVS1 loss-of-function categories, and available splicing evidence does not indicate an abnormal splice effect.

PS1 No PALB2 PS1 splicing comparator evidence was identified to show that this variant produces the same established pathogenic splice effect as a known pathogenic variant.

PS4 No qualifying PALB2 case-control study showing a significant enrichment of this variant in affected individuals was identified.

PM2 This variant is not rare enough for PM2_Supporting under the PALB2 specification.

PM3 No Fanconi anemia proband data or confirmed in trans occurrences with a pathogenic PALB2 variant were identified, so PM3 cannot be scored.

PP1 No segregation data were identified, so PP1 cannot be applied.

PP3 Computational evidence does not support a splice-altering effect.

Benign

BA1 Population frequency is far below the PALB2 BA1 threshold.

BS1 Population frequency does not reach the PALB2 BS1 threshold.

BS2 No qualifying observations in unaffected adults with the required PALB2-specific point-based framework were identified, so BS2 cannot be applied.

BS4 No quantitative non-segregation data were identified.

N/A · 15 PS2 · PS3 · PM1 · PM4 · PM5 · PM6 · PP2 · PP4 · PP5 · BS3 · BP1 · BP2 · BP3 · BP5 · BP6

Research & evidence

Population frequency · supports benign

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 3.71698e-06; MAF= 0.00037%, 6/1614212 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 7.99923e-05; MAF= 0.00800%, 5/62506 alleles, homozygotes = 0).

v2.1

Absent from gnomAD v2.1.

🇨🇦 CA

This variant is present in gnomAD-Canada v1.0 (AF= 0.000108601; MAF= 0.01086%, 2/18416 alleles, homozygotes = 0) and has highest observed frequency in the eas population (AF= 0.00149477; grpmax FAF95= 0.00026546).

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.00037% · 6 / 1,614,212
0 hom

Remaining individuals 5 / 62,506	0.008%
European (non-Finnish) 1 / 1,180,042	8.5e-05%

+ 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 Canada 🇨🇦

0.011% · 2 / 18,416
0 hom · FAF 0.027%

East Asian

2 / 1,338

0.15%

+ 8 not observed (African/African American, Latino/Admixed American, Ashkenazi Jewish, European (Finnish), Middle Eastern, European (non-Finnish), Remaining individuals, South Asian)

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Likely benign (9 clinical laboratories) and as Benign (1 clinical laboratory) and as likely benign (1 clinical laboratory). (ClinVarID = 220617)

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

9Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 9 PMIDs not cited in assessment

25741868 ↗ Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. CLINVAR

26467025 ↗ A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders. CLINVAR

34242744 ↗ Customizing local and systemic therapies for women with early breast cancer: the St. Gallen International Consensus Guidelines for treatment of early breast cancer 2021. CLINVAR

15604628 ↗ Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors. CLINVAR

17508274 ↗ Risk assessment and genetic counseling for hereditary breast and ovarian cancer: recommendations of the National Society of Genetic Counselors. CLINVAR

18163131 ↗ The emerging landscape of breast cancer susceptibility. CLINVAR

20301425 ↗ BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer. CLINVAR

24366376 ↗ Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer in women: U.S. Preventive Services Task Force recommendation statement. CLINVAR

28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR

Re-run this variant?