PALB2c.135G>ALikely benign

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Variant interpretation report

PALB2 c.135G>A, p.(Lys45=)

NM_024675.3:c.135G>A NP_078951.2:p.(Lys45=) 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: 3 supporting (benign) · 1 supporting (pathogenic)
Expert rules: ClinGen PALB2 VCEP v1.2.0

Evidence considered

View criteria

Applied evidence criteria

PM2 (supporting): This variant is present in gnomAD v4.1 at 2/1,614,022 alleles (AF 0.00012%), which is below the PALB2 PM2_Supporting threshold of 0.000333%. This supports PM2 at supporting strength.
BP4 (supporting): SpliceAI predicts no significant splice impact for this variant, with a max delta score of 0.00, which is below the PALB2 BP4 threshold of 0.1. This supports BP4 at supporting strength.
BP6 (supporting): Expert panel ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen classified as Likely benign.
BP7 (supporting): This synonymous PALB2 variant has no predicted splice effect, with SpliceAI max delta score 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: 3

Pathogenic criteria applied · 1

PM2Supporting

PM2 · supporting

This variant is present in gnomAD v4.1 at 2/1,614,022 alleles (AF 0.00012%), which is below the PALB2 PM2_Supporting threshold of 0.000333%. This supports PM2 at supporting strength.

Benign criteria applied · 3

BP4Supporting

BP4 · supporting

SpliceAI predicts no significant splice impact for this variant, with a max delta score of 0.00, which is below the PALB2 BP4 threshold of 0.1. This supports BP4 at supporting strength.

BP6Supporting

BP6 · supporting

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

BP7Supporting

BP7 · supporting

This synonymous PALB2 variant has no predicted splice effect, with SpliceAI max delta score 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, BP6 supporting benign, 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

2 / 1,614,022 alleles

gnomAD v4.1: 2 / 1,614,022 alleles. Recorded AF 1.23914e-06. Recorded homozygote count 0.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 3.97674e-06; MAF= 0.00040%, 1/251462 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.7909e-06; MAF= 0.00088%, 1/113754 alleles, homozygotes = 0).

Applied · PM2 →

gnomAD v4.1 ↗gnomAD v2.1 ↗

No screenshot for this evidence

Computational predictions

Not recorded

No SpliceAI or REVEL score is recorded in the fields used for this tile.

Applied · BP4, BP7 →

ClinVar submissions

Not recorded

A ClinVar laboratory submission summary was not recorded.

Applied · BP6 → 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

Not assessed

No COSMIC evidence statement is recorded in this case.

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: 4 met · 5 not met · 5 not assessed · 14 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.135G>A (p.Lys45=) variant has been reported in ClinVar with an expert panel classification of likely benign.

This variant is present in gnomAD v4.1 at 2/1,614,022 alleles (AF 0.00012%) with a highest observed population frequency of 0.00017% and grpmax FAF 2.8e-07, which is below the PALB2 PM2_Supporting threshold of 0.000333% and below the BS1 and BA1 benign frequency thresholds.

SpliceAI predicts no significant splice impact for this synonymous variant, with a maximum delta score of 0.00, which supports BP4 and argues against PP3 or a splice-based loss-of-function interpretation.

Met · 4

PM2 SupportingThis variant is present in gnomAD v4.1 at 2/1,614,022 alleles (AF 0.00012%), which is below the PALB2 PM2_Supporting threshold of 0.000333%. This supports PM2 at supporting strength. Details ▾Hide ▴

Rule

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

Evidence considered

PALB2 PM2_Supporting threshold ≤0.000333% in gnomAD v4
gnomAD v4.1 total AF 1.23914e-06 (0.00012%)

Sources

cspec ↗gnomad_v4 ↗

BP4 SupportingSpliceAI predicts no significant splice impact for this variant, with a max delta score of 0.00, which is below the PALB2 BP4 threshold of 0.1. This supports BP4 at supporting strength. Details ▾Hide ▴

Rule

For non-missense splicing assessment, no predicted impact via SpliceAI ≤0.1.

Evidence considered

PALB2 BP4 splicing threshold ≤0.1
SpliceAI max delta score 0.00

Sources

cspec ↗spliceai ↗

BP6 SupportingExpert panel ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen classified as Likely benign. Details ▾Hide ▴

Rule

This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.

Evidence considered

PALB2 VCEP marks BP6 not applicable
ClinVar expert panel classification

Sources

cspec ↗clinvar ↗

BP7 SupportingThis synonymous PALB2 variant has no predicted splice effect, with SpliceAI max delta score 0.00. Under the PALB2 specification, this supports BP7 at supporting strength. Details ▾Hide ▴

Rule

Use for synonymous variants; BP7(RNA) may be upgraded when RNA shows no aberrant effect.

Evidence considered

PALB2 BP7 applies to synonymous variants
SpliceAI max delta score 0.00

Still missing

Direct RNA studies for this exact variant were not identified.

Sources

cspec ↗spliceai ↗

Not met · 5 · evaluated, threshold not reached

PVS1 This synonymous variant does not fall within the PALB2 loss-of-function variant categories used for PVS1, and available splicing evidence does not support a loss-of-function effect. SpliceAI predicts no significant splice impact (max delta score 0.00), so PVS1 is not met. Details ▾Hide ▴

Rule

PALB2 PVS1 decision tree; generic scaffold does not support default PVS1 use for this synonymous substitution.

Evidence considered

PALB2 VCEP PVS1 framework
PALB2 is eligible for PVS1 at the gene level
generic PVS1 scaffold does not place this synonymous change in a default null-variant bucket
SpliceAI max delta score 0.00

Still missing

Direct RNA studies for this exact variant were not identified.

Sources

cspec ↗pvs1_gene_contextpvs1_variant_assessmentspliceai ↗

PS4 This variant has been reported in ClinVar, but no case-control study or statistically significant enrichment in affected individuals was identified. The available evidence does not support PS4. Details ▾Hide ▴

Rule

Case-control studies with p-value ≤0.05 and OR/HR/RR ≥3 or lower 95% CI ≥1.5.

Evidence considered

PALB2 VCEP PS4 requires case-control evidence
ClinVar reporting without enrichment data

Still missing

No exact-variant case-control data were identified.

Sources

cspec ↗clinvar ↗

PP3 SpliceAI predicts no significant splice impact for this synonymous variant (max delta score 0.00), which is below the PALB2 PP3 threshold of 0.2. Therefore, PP3 is not met. Details ▾Hide ▴

Rule

For silent, missense/in-frame, and non-canonical intronic variants, predicted splice impact requires SpliceAI ≥0.2.

Evidence considered

PALB2 PP3 splicing threshold ≥0.2
SpliceAI max delta score 0.00

Sources

cspec ↗spliceai ↗

BA1 The gnomAD v4.1 filtering allele frequency is far below the PALB2 BA1 threshold of greater than 0.1%. Therefore, BA1 is not met. Details ▾Hide ▴

Rule

Grpmax filtering AF >0.1% in gnomAD v4 dataset.

Evidence considered

PALB2 BA1 threshold >0.1% in gnomAD v4
gnomAD v4.1 total AF 0.00012%
grpmax FAF 2.8e-07

Sources

cspec ↗gnomad_v4 ↗

BS1 The gnomAD v4.1 frequency is below the PALB2 BS1 threshold of greater than 0.01%. Therefore, BS1 is not met. Details ▾Hide ▴

Rule

Grpmax filtering AF >0.01% in gnomAD v4 dataset.

Evidence considered

PALB2 BS1 threshold >0.01% in gnomAD v4
gnomAD v4.1 total AF 0.00012%
highest observed population AF 0.00017%
grpmax FAF 2.8e-07

Sources

cspec ↗gnomad_v4 ↗

Not assessed · 5 · no assessment recorded

PS1 No evidence was identified showing that this variant has the same established pathogenic splicing effect as a previously classified pathogenic PALB2 variant, so PS1 was not assessed. Details ▾Hide ▴

Rule

Use PALB2 PS1 splicing table when an exact established equivalent splice effect is documented.

Evidence considered

PALB2 VCEP PS1 splicing framework
SpliceAI max delta score 0.00

Still missing

No PALB2 PS1 splicing-table match for this exact variant was identified.

Sources

cspec ↗spliceai ↗

PM3 No evidence was identified that this variant was observed in trans with a pathogenic PALB2 variant in an individual with Fanconi anemia, so PM3 was not assessed. Details ▾Hide ▴

Rule

Use Fanconi anemia PM3 point system when qualifying trans observations are available.

Evidence considered

PALB2 PM3 framework for Fanconi anemia

Still missing

No phase-confirmed recessive case data were identified.