NM_024675.4:c.841A>G

PALB2 · NP_078951.2:p.(Ile281Val) · NM_024675.4

GRCh37: chr16:23647026 T>C · GRCh38: chr16:23635705 T>C

Gene: PALB2 Transcript: NM_024675.4

Final call

BP1 supporting PM2 supporting

Variant details

Gene

PALB2

Transcript

NM_024675.4

Protein

NP_078951.2:p.(Ile281Val)

gnomAD AF

6.195072934593659e-07 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

The PALB2 c.841A>G (p.Ile281Val) variant has been reported in ClinVar as uncertain significance by 2 clinical laboratories.

This variant is absent from gnomAD v2.1 and is present in gnomAD v4.1 at 1/1,614,186 alleles (0.00006%), which is below the PALB2 PM2_Supporting threshold of 0.000333% and far below the BS1 and BA1 thresholds.

SpliceAI predicts no significant splice impact for this variant (max delta score 0.00), and additional computational results are low or benign-leaning (REVEL 0.007; BayesDel -0.722292); however, under the PALB2 VCEP framework PP3 and BP4 are not applied for missense variants, while BP1_Supporting is applied to missense variation in this gene.

Final determination: Rule31 in the Richards et.al., 2015 - Combining rules v1.2.0 criteria-combination framework is satisfied by the adjudicated criteria, so the variant is classified as Uncertain Significance - Conflicting Evidence.

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	No family non-segregation data were identified for this variant, so the PALB2 BS4 LOD/Bayes factor thresholds cannot be evaluated.	cspec
PM4	N/A	This is a missense variant, and the PALB2 VCEP does not apply PM4 to missense changes.	cspec
PM3	Not assessed	No observations were identified showing this variant in trans with a pathogenic or likely pathogenic PALB2 variant in an individual with a recessive PALB2-associated phenotype, so PM3 cannot be assessed.	cspec
BP6	N/A	BP6 is not used by the PALB2 VCEP.	cspec
BP5	N/A	BP5 is not used by the PALB2 VCEP.	cspec
BP1	Met	This is a missense variant, and the PALB2 VCEP applies BP1_Supporting to all missense variants because truncating variants are the primary established disease mechanism in PALB2.	cspec
BS3	N/A	BS3 is not used by the PALB2 VCEP for this variant context.	cspec
BS2	Not assessed	No qualifying observations were identified in unaffected individuals that would allow BS2 point assignment under the PALB2 VCEP.	cspec
BS1	Not met	The highest observed gnomAD v4 frequency is 0.00008% (1/1,180,022 alleles in European non-Finnish), which is below the PALB2 BS1 threshold of greater than 0.01%, so BS1 is not met.	gnomad_v4 cspec
PP4	N/A	PP4 is not used by the PALB2 VCEP for the autosomal dominant cancer predisposition setting.	cspec
PM6	N/A	PM6 is not used by the PALB2 VCEP.	cspec
PM2	Met	This variant is absent from gnomAD v2.1 and is present in gnomAD v4.1 at 1/1,614,186 alleles (0.00006%), which is below the PALB2 PM2_Supporting threshold of 0.000333%, so PM2_Supporting is met.	gnomad_v2 gnomad_v4 cspec
PM1	N/A	PM1 is not used by the PALB2 VCEP because missense pathogenic variation is not an established PALB2 disease mechanism.	cspec
PS4	Not assessed	No case-control data were identified showing this variant is enriched in affected individuals, so the PALB2 PS4 threshold cannot be evaluated.	clinvar cspec
BA1	Not met	The highest observed gnomAD v4 frequency is 0.00008%, which is below the PALB2 BA1 threshold of greater than 0.1%, so BA1 is not met.	gnomad_v4 cspec
PP1	Not assessed	No segregation data were identified for this variant, so PP1 cannot be assessed.	cspec
PVS1	N/A	Although loss of function is an established PALB2 disease mechanism, this variant is a missense substitution that does not fall into the PALB2 or generic PVS1 null-variant categories, and SpliceAI predicts no significant splice impact (max delta score 0.00), so PVS1 is not applicable.	pvs1_gene_context pvs1_variant_assessment spliceai cspec
BP7	N/A	BP7 is intended for synonymous or deep intronic variants, and this variant is missense, so BP7 is not applicable.	cspec
BP4	N/A	SpliceAI predicts no significant splice impact (max delta score 0.00), but the PALB2 VCEP specifies that BP4 should not be applied for missense variants, so BP4 is not applicable here.	spliceai cspec
BP2	N/A	BP2 is not used by the PALB2 VCEP.	cspec
PP2	N/A	PP2 is not used by the PALB2 VCEP because missense variation is not an established PALB2 disease mechanism.	cspec
PS3	N/A	PS3 is not used by the PALB2 VCEP for this variant context.	cspec oncokb
BP3	N/A	BP3 is not used by the PALB2 VCEP for this missense variant context.	cspec
PP5	N/A	PP5 is not used by the PALB2 VCEP.	cspec
PP3	N/A	SpliceAI predicts no significant splice impact (max delta score 0.00), and the PALB2 VCEP specifies that PP3 should not be applied for missense variants, so PP3 is not applicable here. Available missense predictors are also low or benign-leaning (REVEL 0.007; BayesDel -0.722292), but PALB2 missense PP3 is not used under this framework.	spliceai revel bayesdel cspec
PM5	N/A	PM5 is not applicable because the PALB2 VCEP does not use classic same-residue missense PM5 for missense variants, and the PM5 framework for PALB2 is limited to truncating or qualifying splice variants upstream of p.Tyr1183.	cspec pm5_candidates
PS2	N/A	PS2 is not used by the PALB2 VCEP.	cspec
PS1	N/A	PS1 is not applicable because the PALB2 VCEP does not use PS1 for missense changes, and no splice-based PS1 comparator evidence was identified.	cspec spliceai

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