NM_024675.4:c.721A>G

PALB2 · NP_078951.2:p.(Asn241Asp) · NM_024675.4

GRCh37: chr16:23647146 T>C · GRCh38: chr16:23635825 T>C

Gene: PALB2 Transcript: NM_024675.4

Final call

Benign

BA1 BS1 BP1

Variant details

Gene

PALB2

Transcript

NM_024675.4

Protein

NP_078951.2:p.(Asn241Asp)

gnomAD AF

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

The PALB2 VCEP specification defines BA1 at gnomAD v4 grpmax filtering AF >0.1%, BS1 at >0.01%, and BP1 for all missense variants.

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.

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.

Final determination:

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
BS4	Not assessed	PALB2 BS4 is applicable, but no quantitative segregation or lack-of-segregation data were assembled in the workspace for this variant.
PM4	N/A	PALB2 PM4 is not applicable for this missense substitution; the specification limits PM4 to stop-loss variants.	cspec
PM3	Not assessed	PALB2 PM3 requires Fanconi anemia-style in trans evidence with scoring; no such case-level biallelic data were provided in the workspace.
BP6	N/A	BP6 is explicitly not for use by this VCEP.	cspec
BP5	N/A	BP5 is explicitly not applicable for PALB2 under this VCEP.	cspec
BP1	Met	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.	cspec
BS3	N/A	BS3 is marked not applicable in the PALB2 VCEP materials provided in this workspace.	cspec
BS2	Not assessed	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.
BS1	Met	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 cspec
PP4	N/A	PP4 is not applicable for PALB2-related cancer predisposition in this VCEP framework.	cspec
PM6	N/A	PM6 is not applicable for PALB2 under this VCEP.	cspec
PM2	Not met	PALB2 PM2_Supporting requires frequency ≤ 1/300,000 (0.000333%) in gnomAD v4. The workspace reports total AF 0.0003326799507361086, which is approximately 0.03327%, well above the PM2 threshold.	gnomad_v4 cspec
PM1	N/A	PM1 is not applicable in PALB2 because missense pathogenic variation is not yet confirmed as a disease mechanism under this specification.	cspec
PS4	Not assessed	PS4 requires a qualifying case-control result. The workspace does not provide a p-value plus odds ratio/hazard ratio/relative risk meeting PALB2 PS4 thresholds for this specific variant.
BA1	Met	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 cspec
PP1	Not assessed	PP1 requires quantitative cosegregation or defined AR segregation counts. No such segregation analysis was present in the workspace.
PVS1	Not met	This is a missense substitution with no predicted splice impact (SpliceAI max delta 0.00), so PALB2 PVS1 does not apply.	spliceai cspec
BP7	Not met	BP7 is intended for synonymous/deep intronic variants or qualifying RNA evidence for silent/intronic variants; this variant is missense.	cspec
BP4	Not met	Although SpliceAI predicts no splice impact (0.00), the PALB2 VCEP explicitly states BP4 should not be applied for missense variants.	spliceai cspec
BP2	N/A	BP2 is not applicable for PALB2 in this VCEP framework.	cspec
PP2	N/A	PP2 is not applicable for PALB2 because missense is not an established disease mechanism in this specification.	cspec
PS3	N/A	PS3 is marked not applicable in the PALB2 VCEP materials supplied in the workspace.	cspec
BP3	N/A	BP3 is not applicable for PALB2 under this VCEP.	cspec
PP5	N/A	PP5 is explicitly not for use by this VCEP.	cspec
PP3	Not met	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.	spliceai cspec
PM5	Not met	PALB2 PM5_Supporting is not to be used for missense changes; it is reserved for truncating/splice contexts described in the specification.	cspec
PS2	N/A	PS2 is not applicable for PALB2 under this VCEP.	cspec
PS1	Not met	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.	cspec spliceai

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.