NM_024675.4:c.2945G>T

PALB2 · NP_078951.2:p.(Gly982Val) · NM_024675.4

GRCh37: chr16:23634341 C>A · GRCh38: chr16:23623020 C>A

Gene: PALB2 Transcript: NM_024675.4

Final call

VUS

PM2 supporting BP1 supporting

Variant details

Gene

PALB2

Transcript

NM_024675.4

Protein

NP_078951.2:p.(Gly982Val)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

PM2 (Supporting): absent from gnomAD v4.1 exomes (AF 0), below the <=1/300,000 VCEP frequency threshold.

BP1 (Supporting): the PALB2 VCEP applies BP1 to all missense variants given the low rate of pathogenic missense changes in PALB2.

Overall: VUS (Uncertain Significance - Conflicting Evidence), per Rule 31 combining PM2 (Pathogenic.Supporting) with BP1 (Benign.Supporting).

Final determination: Under the ClinGen HBOPC PALB2 VCEP v1.2 combination rules, the presence of at least one pathogenic-supporting criterion (PM2 supporting) together with at least one benign-supporting criterion (BP1 supporting) satisfies Rule31 (Benign.Supporting >=1 AND Pathogenic.Supporting >=1), which maps to Uncertain Significance - Conflicting Evidence (VUS); no higher-evidence pathogenic or benign rule is satisfied.

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
PVS1	N/A	Not applicable: this is a missense substitution (p.(Gly982Val)) with no predicted splice effect (SpliceAI max delta 0.003), so no null-variant consequence exists.	cspec pvs1_variant_assessment pvs1_gene_context pvs1_generic_framework spliceai
PS1	N/A	Not applicable: the PALB2 VCEP restricts PS1 to splicing variants, and this missense change (p.(Gly982Val), SpliceAI max delta 0.003) triggers no splicing scenario.	cspec spliceai clinvar
PS2	N/A	Not applicable: the PALB2 VCEP disallows PS2 for both AD and AR disease, and no de novo or parental-testing data exist.	cspec
PS3	N/A	Not applicable: the PALB2 VCEP defines no PS3 rule, and no functional studies of p.(Gly982Val) are available.	cspec oncokb
PS4	Not met	Not met: PS4 requires a case-control study (p <= 0.05, OR >= 3), and no case-control or enrichment data exist for this variant.	cspec
PM1	N/A	Not applicable: the PALB2 VCEP disallows PM1 for missense variants, and p.(Gly982Val) is not in a cancer hotspot.	cspec
PM2	Met	Met (Supporting): absent from gnomAD v4.1 exomes (AF 0), satisfying the VCEP frequency threshold of <=1/300,000.	cspec gnomad_v4 gnomad_v2 gnomad_canada
PM3	Not assessed	Not assessed: no proband, family, or phase data were available to determine whether the variant occurs in trans with a pathogenic PALB2 allele.	cspec clinvar
PM4	N/A	Not applicable: PM4 covers in-frame indels or stop-loss variants, and this missense change preserves the reading frame and protein length.	cspec pvs1_variant_assessment spliceai
PM5	N/A	Not applicable: the PALB2 VCEP restricts PM5 to truncating variants upstream of p.Tyr1183, not missense changes.	cspec pm5_candidates
PM6	N/A	Not applicable: the PALB2 VCEP disallows PM6 for both AD and AR disease, as de novo occurrences are not yet informative.	cspec
PP1	Not assessed	Not assessed: no family or segregation data were available to compute the required LOD >= 0.3 or Bayes factor >= 2:1.	cspec clinvar
PP2	N/A	Not applicable: the PALB2 VCEP disallows PP2, as missense is not yet confirmed as a disease mechanism for PALB2.	cspec
PP3	Not met	Not met: splice-based PP3 requires SpliceAI >= 0.2, and the max delta is 0.003; the VCEP prohibits missense predictors.	cspec spliceai revel bayesdel
PP4	N/A	Not applicable: the PALB2 VCEP declares PP4 not applicable, so phenotype specificity is not used as a criterion.	cspec
PP5	N/A	Not applicable: the PALB2 VCEP disallows PP5, and the variant is absent from ClinVar so no expert-panel classification exists.	cspec clinvar
BA1	Not met	Not met: BA1 requires gnomAD filtering AF > 0.1%, and the variant is absent (AF 0).	cspec gnomad_v4 gnomad_v2 gnomad_canada
BS1	Not met	Not met: BS1 requires gnomAD filtering AF > 0.01%, and the variant is absent (AF 0).	cspec gnomad_v4 gnomad_v2 gnomad_canada
BS2	Not met	Not met: no observations of this variant in individuals inconsistent with the expected phenotype exist; it is absent from gnomAD and ClinVar.	cspec gnomad_v4 gnomad_v2 gnomad_canada clinvar
BS3	N/A	Not applicable: the PALB2 VCEP defines no BS3 rule, and no functional assay evidence exists for this variant.	cspec oncokb
BS4	Not assessed	Not assessed: no non-segregation data were available to compute the required LOD <= -0.32 or LR <= 0.48.	cspec clinvar
BP1	Met	Met (Supporting): the PALB2 VCEP applies BP1 to all missense variants, including p.(Gly982Val), given the low rate of pathogenic missense changes.	cspec
BP2	N/A	Not applicable: the PALB2 VCEP marks BP2 not applicable, so it is not used in this framework.	cspec
BP3	N/A	Not applicable: BP3 covers in-frame indels in non-functional repeat regions, and this variant is a missense substitution.	cspec pvs1_variant_assessment spliceai
BP4	N/A	Not applicable: the PALB2 VCEP forbids BP4 for missense variants despite SpliceAI max delta 0.003 and REVEL 0.158.	cspec spliceai revel bayesdel
BP5	N/A	Not applicable: the PALB2 VCEP declares BP5 not applicable, so an alternate-molecular-basis rule is not used.	cspec
BP6	N/A	Not applicable: the PALB2 VCEP disallows BP6, and the variant is absent from ClinVar so no expert-panel benign classification exists.	cspec clinvar
BP7	N/A	Not applicable: BP7 applies to synonymous and deep intronic variants, and this is a missense change in exon 9.	cspec

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