Classification rationale

PM2 BP1 Uncertain Significance - Conflicting Evidence

PALB2 c.841A>G

The PALB2 c.841A>G (p.Ile281Val) variant has been reported in ClinVar as uncertain significance by 2 clinical laboratories.¹ This variant is absent from gnomAD v2.1 and is present in gnomAD v4.1 at 1/1,614,186 alleles (0.00006%), which is below the PALB2 PM2_Supporting threshold of 0.000333% and far below the BS1 and BA1 thresholds.² SpliceAI predicts no significant splice impact for this variant (max delta score 0.00), and additional computational results are low or benign-leaning (REVEL 0.007; BayesDel -0.722292); however, under the PALB2 VCEP framework PP3 and BP4 are not applied for missense variants, while BP1_Supporting is applied to missense variation in this gene.³

PM2 + BP1 → Uncertain Significance - Conflicting Evidence

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗cspec ↗

3 spliceai ↗revelbayesdelcspec ↗

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_024675.4 · variants mapped to exon structure

PALB2 NM_024675.4

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 7 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 · 2

Strength Supporting Moderate Strong Very strong

PM2 supporting Pathogenic

This variant is absent from gnomAD v2.1 and is present in gnomAD v4.1 at 1/1,614,186 alleles (0.00006%), which is below the PALB2 PM2_Supporting threshold of 0.000333%, so PM2_Supporting is met.

Absent from gnomAD v2.1.gnomAD v4 total AF 0.00006% (1/1614

gnomad_v2 ↗gnomad_v4 ↗cspec ↗

BP1 supporting Benign

This is a missense variant, and the PALB2 VCEP applies BP1_Supporting to all missense variants because truncating variants are the primary established disease mechanism in PALB2.

Variant consequence: missense p.(Ile281Val).PALB2 VCEP BP1 rule: apply to all missense variants.

cspec ↗

Assessed · not applied · 2 not met · 5 not assessed

Pathogenic

PS4 No case-control data were identified showing this variant is enriched in affected individuals, so the PALB2 PS4 threshold cannot be evaluated.

PM3 No observations were identified showing this variant in trans with a pathogenic or likely pathogenic PALB2 variant in an individual with a recessive PALB2-associated phenotype, so PM3 cannot be assessed.

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

Benign

BA1 The highest observed gnomAD v4 frequency is 0.00008%, which is below the PALB2 BA1 threshold of greater than 0.1%, so BA1 is not met.

BS1 The highest observed gnomAD v4 frequency is 0.00008% (1/1,180,022 alleles in European non-Finnish), which is below the PALB2 BS1 threshold of greater than 0.01%, so BS1 is not met.

BS2 No qualifying observations were identified in unaffected individuals that would allow BS2 point assignment under the PALB2 VCEP.

BS4 No family non-segregation data were identified for this variant, so the PALB2 BS4 LOD/Bayes factor thresholds cannot be evaluated.

N/A · 19 PVS1 · PS1 · PS2 · PS3 · PM1 · PM4 · PM5 · PM6 · PP2 · PP3 · PP4 · PP5 · BS3 · BP2 · BP3 · BP4 · BP5 · BP6 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 6.19507e-07; MAF= 0.00006%, 1/1614186 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47442e-07; MAF= 0.00008%, 1/1180022 alleles, homozygotes = 0).

v2.1

Absent from gnomAD v2.1.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

6.2e-05% · 1 / 1,614,186
0 hom

European (non-Finnish)

1 / 1,180,022

8.5e-05%

+ 9 not observed (Remaining individuals, 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 (2 clinical laboratories). (ClinVarID = 530108)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.007. BayesDel score = -0.722292.

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 previously been reported in somatic cancers (COSMIC; COSV55171918, n = 1 times).

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

Triaged references · 9 PMIDs not cited in assessment

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

24366402 ↗ Summaries for patients. Assessing the genetic risk for BRCA-related breast or ovarian cancer in women: recommendations from the U.S. Preventive Services Task Force. CLINVAR

24432435 ↗ PMID:24432435 CLINVAR

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

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