Classification rationale

PM2 BP4BP7 Likely Benign

PALB2 c.1578T>C

The PALB2 c.1578T>C (p.His526=) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar with benign or likely benign single-submitter classifications.¹ This variant is absent from gnomAD v2.1 and gnomAD v4.1, placing its observed population frequency at 0%, below the PALB2 PM2_Supporting threshold of 0.000333%.² In silico splice prediction shows no evidence of splice disruption, with a SpliceAI maximum delta score of 0.00; this is below the PALB2 BP4 threshold of 0.1 and well below the PP3 threshold of 0.2, supporting BP4 and BP7 rather than PP3.³

PM2 + BP4 + BP7 → Likely Benign

1 clinvar ↗

2 gnomad_v2 ↗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_024675.4 · variants mapped to exon structure

PALB2 NM_024675.4

Fetching transcript structure from UCSC…

Applied criteria · 3 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 · 3

Strength Supporting Moderate Strong Very strong

PM2 supporting Pathogenic

This variant is absent from gnomAD v4.1 and gnomAD v2.1. The observed population frequency is therefore 0%, which is below the PALB2 PM2_Supporting threshold of 0.000333% (1 in 300,000).

Absent from gnomAD v4.1.Absent from gnomAD v2.1.PALB2 PM2 is applied at Supporting strength only when frequency is ≤0.000333% in gnomAD v4.

gnomad_v4 ↗gnomad_v2 ↗cspec ↗

BP4 supporting Benign

SpliceAI predicts no splice impact for this variant, with a maximum delta score of 0.00. This is below the PALB2 BP4 threshold of 0.1, supporting no computational evidence for abnormal splicing.

SpliceAI max delta score is 0.00.PALB2 BP4 for splicing is met when SpliceAI is ≤0.1.

spliceai ↗cspec ↗

BP7 supporting Benign

This variant is a synonymous change, p.(His526=), and SpliceAI predicts no splice impact with a maximum delta score of 0.00. Under the PALB2 specification, this supports BP7 at Supporting strength.

The variant is synonymous: p.(His526=).SpliceAI max delta score is 0.00.PALB2 BP7 applies to synonymous variants and silent variants with no observed or predicted splice defect.

cspec ↗spliceai ↗clinvar ↗

Assessed · not applied · 4 not met · 6 not assessed

Pathogenic

PVS1 This synonymous variant does not fall into the PALB2 loss-of-function or canonical splice categories used for PVS1, and SpliceAI predicts no splice disruption (max delta score 0.00).

PS1 No evidence was identified that this variant matches a PALB2 PS1 splicing-table comparator with the same predicted or observed splice effect as an established pathogenic variant.

PS4 No case-control study or other quantitative enrichment data were identified showing that this variant is significantly more common in affected individuals than in controls.

PM3 No observations were identified showing this variant in trans with a pathogenic PALB2 variant in an individual with Fanconi anemia, so PM3 cannot be assessed from the available evidence.

PP1 No segregation data were identified for this variant, so PALB2 PP1 cannot be assessed.

PP3 SpliceAI predicts no splice impact for this variant, with a maximum delta score of 0.00.

Benign

BA1 This variant is absent from gnomAD v4.1, so its observed population frequency is 0%.

BS1 This variant is absent from gnomAD v4.1, so its observed population frequency is 0%.

BS2 No qualifying observations were identified in unaffected individuals that would allow BS2 scoring under the PALB2 Fanconi anemia framework.

BS4 No quantitative non-segregation data were identified for this variant, so BS4 cannot be assessed.

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

Absent from gnomAD v4.1.

v2.1

Absent from gnomAD v2.1.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

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 Likely benign (2 clinical laboratories) and as Benign (1 clinical laboratory). (ClinVarID = 795606)

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

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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