Classification rationale

BP1BS1BA1 Benign

PALB2 c.721A>G

The PALB2 VCEP specification defines BA1 at gnomAD v4 grpmax filtering AF >0.1%, BS1 at >0.01%, and BP1 for all missense variants.¹ In the assembled workspace, gnomAD v4 reports grpmax_faf 0.00602134 (~0.602%), which exceeds both the BA1 and BS1 PALB2 thresholds by a wide margin.² The variant is a missense substitution p.(Asn241Asp)/p.(N241D), so PALB2-specific BP1 also applies; ClinVar expert-panel benign classification is concordant but was not needed as an ACMG criterion because BA1 alone is sufficient for a benign call.³

BP1 + BS1 + BA1 → Benign

1 cspec ↗

2 gnomad_v4 ↗

3 clinvar ↗

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 · 12 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

BP1 Supporting review Benign

This is a missense variant, and the PALB2 VCEP specification states BP1 applies to all missense variants because pathogenic missense variation is thought to be exceedingly rare in PALB2.

NM_024675.4:c.721A>G = NP_078951.2:p.(Asn241Asp), a missense change.PALB2 BP1 rule: apply to all missense variants.

cspec ↗

BS1 Strong review Benign

PALB2 BS1 is met when gnomAD v4 grpmax filtering AF exceeds 0.01%. The workspace reports gnomAD v4 grpmax_faf 0.00602134, which is approximately 0.602%, far above the BS1 threshold.

gnomAD v4 source_data.grpmax_faf = 0.006021340000000001 (~0.602%).PALB2 BS1 threshold: grpmax filtering AF >0.01% in gnomAD v4.

gnomad_v4 ↗cspec ↗

BA1 Stand Alone review Benign

PALB2 BA1 is met when gnomAD v4 grpmax filtering AF exceeds 0.1%. The workspace reports grpmax_faf 0.00602134, which is approximately 0.602%, comfortably above the BA1 threshold.

gnomAD v4 source_data.grpmax_faf = 0.006021340000000001 (~0.602%).PALB2 BA1 threshold: grpmax filtering AF >0.1% in gnomAD v4.

gnomad_v4 ↗cspec ↗

Assessed · not applied · 7 not met · 5 not assessed

Pathogenic

PM3 PALB2 PM3 requires Fanconi anemia-style in trans evidence with scoring; no such case-level biallelic data were provided in the workspace.

PM2 PALB2 PM2_Supporting requires frequency ≤ 1/300,000 (0.000333%) in gnomAD v4.

PS4 PS4 requires a qualifying case-control result.

PP1 PP1 requires quantitative cosegregation or defined AR segregation counts.

PVS1 This is a missense substitution with no predicted splice impact (SpliceAI max delta 0.00), so PALB2 PVS1 does not apply.

PP3 SpliceAI does not predict splice impact (max delta 0.00), and the PALB2 VCEP also states PP3 should not be used for missense prediction itself.

PM5 PALB2 PM5_Supporting is not to be used for missense changes; it is reserved for truncating/splice contexts described in the specification.

PS1 For PALB2, PS1 is not used for missense changes and instead only via the PALB2 splicing table where applicable; no splicing-based PS1 evidence exists here.

Benign

BS4 PALB2 BS4 is applicable, but no quantitative segregation or lack-of-segregation data were assembled in the workspace for this variant.

BS2 BS2 requires scored observations in healthy adults/co-occurrence framework per PALB2 FA tables; the workspace does not provide the necessary curated individual-level evidence.

BP7 BP7 is intended for synonymous/deep intronic variants or qualifying RNA evidence for silent/intronic variants; this variant is missense.

BP4 Although SpliceAI predicts no splice impact (0.00), the PALB2 VCEP explicitly states BP4 should not be applied for missense variants.

N/A · 13 PM4 · BP6 · BP5 · BS3 · PP4 · PM6 · PM1 · BP2 · PP2 · PS3 · BP3 · PP5 · PS2

Research & evidence

Population frequency · supports benign

gnomAD v4.1

gnomAD v2.1

Allele frequency by ancestry

three datasets · side by side

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Benign (9 clinical laboratories) and as Likely benign (8 clinical laboratories) and as Benign by ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen (expert panel).

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

SpliceAI ↗

Functional

OncoKB classifies this variant as Inconclusive; biological effect: Inconclusive.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence

COSMIC

This variant has previously been reported in somatic cancers (COSMIC; COSV104552978, n = 1 times).

Hotspots

This variant does not lie in a statistically significant cancer hotspot.

Sources & reference links

6Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

Check your email

Reset your password

Enter an access code

Your allowance