PALB2c.1578T>CLikely benign

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Variant interpretation report

PALB2 c.1578T>C, p.(His526=)

NM_024675.4:c.1578T>C NP_078951.2:p.(His526=) View identifiers

Classification

Likely benign

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is likely benign. Select a step to read what it means.

Likely benign.A likely benign classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About PALB2

No gene-level summary was recorded for this case.

Key facts

Evidence used: 2 supporting (benign) · 1 supporting (pathogenic)
Expert rules: ClinGen PALB2 VCEP v1.2.0
Other laboratories (ClinVar): 2 Likely benign · 1 Benign
Pipeline record: 24 May 2026

Evidence considered

View criteria

Applied evidence criteria

PM2 (supporting): 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).
BP4 (supporting): 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.
BP7 (supporting): 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.

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.

01The reasoning

How it was classified

The recorded framework is ClinGen PALB2 VCEP v1.2.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 1 Benign evidence criteria: 2

Pathogenic criteria applied · 1

PM2Supporting

PM2 · supporting

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).

Benign criteria applied · 2

BP4Supporting

BP4 · supporting

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.

BP7Supporting

BP7 · supporting

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.

Recorded classification: Likely benign

Richards et.al., 2015 - Combining rules v1.2.0 criteria-combination framework: matched Rule19 (Benign.Supporting >=2) with applied criteria: PM2 supporting, BP4 supporting, BP7 supporting; maps to Likely Benign.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

gnomAD v4.1

gnomAD v2.1

Population frequency

Not recorded

gnomAD v4.1 allele counts were not recorded for this variant.

gnomAD v2.1

Absent from gnomAD v2.1.

Applied · PM2 →

gnomAD v4.1 ↗gnomAD v2.1 ↗

SpliceAI score

0.000 maximum delta

Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4, BP7 → SpliceAI ↗

ClinVar submissions

3 reported laboratory submissions

2 Likely benign · 1 Benign.

Context only ClinVar ↗

Functional evidence

Statement recorded

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

No listed criterion applied OncoKB ↗

COSMIC

Cancer Hotspots

Somatic evidence

No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only

COSMIC ↗Cancer Hotspots ↗

For specialists

Technical detail

ACMG/AMP criteria under ClinGen PALB2 VCEP v1.2.0, with the data and sources behind each one.

28 criteria with recorded statuses: 3 met · 4 not met · 6 not assessed · 15 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5

Benign

BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7

Met Not met Not assessed Not applicable

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.

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%.

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.

Met · 3

PM2 SupportingThis 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). Details ▾Hide ▴

Rule

Frequency ≤ 1/300,000 (0.000333%) in gnomAD v4 dataset

Evidence considered

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.

Sources

gnomad_v4 ↗gnomad_v2 ↗cspec ↗

BP4 SupportingSpliceAI 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. Details ▾Hide ▴

Rule

Splicing: no predicted impact via splicing (SpliceAI ≤0.1). Do not apply for missense variants.

Evidence considered

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

Sources

spliceai ↗cspec ↗

BP7 SupportingThis 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. Details ▾Hide ▴

Rule

Use for synonymous variants; BP7(RNA) may also be used for lack of aberrant RNA defect.

Evidence considered

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.

Sources

cspec ↗spliceai ↗clinvar ↗

Not met · 4 · evaluated, threshold not reached

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). Details ▾Hide ▴

Rule

Use PALB2 PVS1 Decision Tree

Evidence considered

PALB2 has gene-level PVS1 eligibility in the CSPEC framework.
c.1578T>C is a synonymous change
p.(His526=).
Generic PVS1 scaffold does not place this variant in a null-variant bucket.
SpliceAI max delta score is 0.00.

Sources

cspec ↗pvs1_gene_contextpvs1_variant_assessmentspliceai ↗

PP3 SpliceAI predicts no splice impact for this variant, with a maximum delta score of 0.00. This is below the PALB2 PP3 threshold of 0.2, so computational evidence does not support a damaging splicing effect. Details ▾Hide ▴

Rule

Splicing: predicted impact via splicing (SpliceAI ≥0.2) for silent, missense/in-frame, and intronic variants outside ±1,2.

Evidence considered

SpliceAI DS_AG 0.0
DS_AL 0.0
DS_DG 0.0
DS_DL 0.0
max delta 0.00.
PALB2 PP3 for non-canonical splice-relevant variants requires SpliceAI ≥0.2.

Sources

spliceai ↗cspec ↗

BA1 This variant is absent from gnomAD v4.1, so its observed population frequency is 0%. This is below the PALB2 BA1 threshold of more than 0.1%, so BA1 is not met. Details ▾Hide ▴

Rule

Grpmax Filtering AF >0.1% in gnomAD v4 dataset

Evidence considered

Absent from gnomAD v4.1.
PALB2 BA1 requires grpmax filtering allele frequency >0.1% in gnomAD v4.

Sources

gnomad_v4 ↗cspec ↗

BS1 This variant is absent from gnomAD v4.1, so its observed population frequency is 0%. This is below the PALB2 BS1 threshold of more than 0.01%, so BS1 is not met. Details ▾Hide ▴

Rule

Grpmax Filtering AF >0.01% in gnomAD v4 dataset

Evidence considered

Absent from gnomAD v4.1.
PALB2 BS1 requires grpmax filtering allele frequency >0.01% in gnomAD v4.

Sources

gnomad_v4 ↗cspec ↗

Not assessed · 6 · no assessment recorded

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. Details ▾Hide ▴

Rule

Use PALB2 PS1 Splicing table

Evidence considered

PALB2 PS1 requires use of a gene-specific splicing table.
SpliceAI shows no predicted splice impact for this variant.

Still missing

No qualifying PALB2 PS1 splicing comparator was identified in the available evidence.

Sources

cspec ↗spliceai ↗

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. ClinVar contains benign or likely benign single-submitter assertions, but these do not satisfy the PALB2 PS4 requirement. Details ▾Hide ▴

Rule

Case-control studies; p-value ≤0.05 AND (odds ratio, hazard ratio, or relative risk ≥3 OR lower 95% CI ≥1.5).

Evidence considered

ClinVar includes 3 single-submitter benign/likely benign classifications.
No validated PS4-ready case-control evidence was identified.

Still missing

No qualifying case-control statistics meeting the PALB2 PS4 threshold were identified.

Sources

clinvar ↗cspec ↗

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. Details ▾Hide ▴

Rule

Apply PM3 strength by Fanconi anemia point totals.

Evidence considered

PALB2 PM3 requires Fanconi anemia proband-based scoring.

Still missing

No phase-confirmed Fanconi anemia proband data were identified.