Classification rationale

PM2 BP1 VUS

PALB2 c.2970A>T missense · exon 9

PM2 (Supporting): absent from gnomAD v4 (AF = 0), below the VCEP's <=1/300,000 (0.000333%) frequency threshold. BP1 (Supporting): the VCEP applies BP1 to all missense variants, and c.2970A>T is a confirmed missense change (p.Glu990Asp). Overall: VUS — Rule 31, conflicting evidence combining one Pathogenic.Supporting (PM2) and one Benign.Supporting (BP1) criterion.

PM2 + BP1 → VUS

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

PALB2 NM_024675.4

Fetching transcript structure from UCSC…

Applied criteria · 2 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 · 2

Strength Supporting Moderate Strong Very strong

PM2 supporting Pathogenic

Met (Supporting): absent from gnomAD v4 (AF=0), satisfying the VCEP frequency threshold of <=1/300,000 (0.000333%).

ClinGen HBOPC VCEP PALB2 v1.2 CSPEC PM2 rule: 'Frequency <= 1/300,000 (0.000333%) in gnomAD v4 dataset'; instructions specify 'Use as PM2_Supporting (not moderate)'.gnomAD v4.1 (GRCh38) lookup for chr16-23622995-T-A returned no variant record (search_status=absent), i.e., AF = 0, which is <= the 0.000333% PM2 threshold.Corroborating absence in gnomAD v2.1 (16-23634316-T-A) and gnomAD-Canada v1.0 (HostSeq genomes).

cspec ↗gnomad_v4 ↗gnomad_v2 ↗gnomad_canada ↗

BP1 supporting Benign

Met (Supporting): the VCEP applies BP1 to all missense variants; this is a confirmed missense change (p.Glu990Asp).

PALB2 HBOP VCEP v1.2 (cspec) BP1 rule: 'Apply to all missense variants.' with default strength Benign Supporting.Variant normalization confirms a missense change: NP_078951.2:p.(Glu990Asp) from c.2970A>T; pvs1_variant_assessment consequence_class is 'missense'.

cspec ↗

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

Pathogenic

PVS1 Not met: missense substitution with no protein length change and no predicted splice impact (SpliceAI max delta 0.026, below the 0.2 threshold).

PS1 Not met: no predicted splice impact (SpliceAI max delta 0.026), so the VCEP's splicing-based PS1 does not apply.

PS4 Not assessed: no case-control or prevalence data existed to evaluate enrichment (threshold OR >=3, p <=0.05).

PM3 Not assessed: no proband, allele, or phase observations existed, so no Fanconi anemia PM3 points could be assigned.

PP1 Not assessed: no pedigree, LOD, or segregation data existed (Supporting requires LOD >=0.3), pending family studies.

PP3 Not met: SpliceAI max delta 0.026 is below the VCEP's 0.2 threshold, and missense in-silico predictors are barred for PP3.

Benign

BA1 Not met: absent from gnomAD v4 (AF=0), below the VCEP BA1 threshold of >0.1%.

BS1 Not met: absent from gnomAD v4 (AF=0), below the VCEP BS1 threshold of >0.01%.

BS2 Not met: no observed instances in healthy adults, so 0 BS2 points accrued (>=4 required for Strong).

BS4 Not assessed: no pedigree or segregation data existed to test lack of segregation (LOD <=-0.32 at Supporting).

N/A · 16 PS2 · PS3 · PM1 · PM4 · PM5 · PM6 · PP2 · PP4 · PP5 · BS3 · BP2 · BP3 · BP4 · BP5 · BP6 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

Absent from gnomAD v4.1.

v2.1

Absent from gnomAD v2.1.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

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 Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant is absent from ClinVar.

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.014. BayesDel score = -0.568457.

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 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