NM_024675.4:c.1432T>C

PALB2 · NP_078951.2:p.(Ser478Pro) · NM_024675.4

GRCh37: chr16:23646435 A>G · GRCh38: chr16:23635114 A>G

Gene: PALB2 Transcript: NM_024675.4

Final call

PM2 supporting BP1 supporting

Variant details

Gene

PALB2

Transcript

NM_024675.4

Protein

NP_078951.2:p.(Ser478Pro)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

The PALB2 c.1432T>C (p.Ser478Pro) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar with conflicting germline submissions, including uncertain significance and likely benign interpretations.

This variant is absent from gnomAD v2.1 and gnomAD v4.1; the observed frequency is therefore below the PALB2 PM2_Supporting threshold of ≤0.000333% and below the benign population thresholds for BS1 and BA1.

SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.01, which is below the PALB2 splice thresholds used for PP3 (≥0.2) and BP4 (≤0.1), although PP3 and BP4 are not applied to missense variants under the PALB2 specification.

Under the PALB2 expert specification, BP1_Supporting is met because this is a missense variant in a gene where disease is primarily associated with truncating variants, while PVS1 is not met because this variant is not a qualifying loss-of-function change.

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
PVS1	Not met	This missense variant does not fall into the PALB2 loss-of-function categories used for PVS1. The variant-level assessment states that c.1432T>C is not a nonsense, frameshift, or canonical ±1/2 splice-site variant, so PVS1 is not applied.	cspec pvs1_gene_context pvs1_variant_assessment
PS1	N/A	The PALB2 specification does not use PS1 for missense changes. PS1 is reserved for splice-based equivalence using the PALB2 PS1 splicing table, and no such splice evidence was identified for this missense variant.	cspec spliceai
PS2	N/A	The PALB2 specification does not use PS2 for this gene-disease context. No informative confirmed de novo evidence is used for PALB2-related cancer predisposition in this framework.	cspec
PS3	N/A	The PALB2 specification does not apply PS3 for this variant type in this framework. No PALB2 protein functional study meeting an applicable PS3 rule was identified.	cspec
PS4	Not assessed	Available evidence does not show a PALB2 case-control study for this variant meeting the PS4 threshold of p≤0.05 with odds ratio, hazard ratio, or relative risk ≥3 or lower 95% confidence interval ≥1.5. ClinVar submissions alone do not satisfy this requirement.	cspec clinvar
PM1	N/A	The PALB2 specification does not use PM1 because missense pathogenic variation is not yet established as a disease mechanism in PALB2. This variant is therefore not evaluated under PM1.	cspec
PM2	Met	This variant is absent from gnomAD v4.1, so the observed population frequency is 0%, which is below the PALB2 PM2_Supporting threshold of ≤0.000333% (1 in 300,000). The variant is also absent from gnomAD v2.1.	cspec gnomad_v4 gnomad_v2
PM3	Not assessed	No data were identified showing this variant in trans with a pathogenic PALB2 variant in a proband with Fanconi anemia, so PM3 cannot be evaluated.	cspec
PM4	N/A	PM4 is not applicable because this variant is a missense substitution and not a stop-loss variant or qualifying in-frame length-changing variant under the PALB2 specification.	cspec
PM5	N/A	The PALB2 specification limits PM5 to truncating or certain splice variants and states that missense changes should not use PM5. This missense variant therefore does not qualify.	cspec
PM6	N/A	The PALB2 specification does not use PM6 for this gene-disease context. No assumed de novo evidence is used in this framework.	cspec
PP1	Not assessed	No segregation data were identified for this variant, so the PALB2 quantitative co-segregation thresholds for PP1 were not met or evaluated.	cspec
PP2	N/A	The PALB2 specification does not use PP2 because missense variation is not established as a common pathogenic mechanism in PALB2.	cspec
PP3	N/A	The PALB2 specification does not use PP3 for missense variants. Although SpliceAI predicts no significant splice effect with a maximum delta score of 0.01, the PP3 splice threshold is ≥0.2 and missense variants are excluded from PP3 use in this framework.	cspec spliceai
PP4	N/A	The PALB2 specification does not use PP4 for autosomal dominant PALB2-related cancer predisposition because the phenotype is not sufficiently specific for a single genetic cause.	cspec
PP5	N/A	PP5 is not used by this VCEP. External assertions without independently reviewable evidence are not applied in the PALB2 specification.	cspec
BA1	Not met	This variant is absent from gnomAD v4.1, so the observed population frequency is 0%, which is below the PALB2 BA1 threshold of >0.1%. BA1 is not met.	cspec gnomad_v4
BS1	Not met	This variant is absent from gnomAD v4.1, so the observed population frequency is 0%, which is below the PALB2 BS1 threshold of >0.01%. BS1 is not met.	cspec gnomad_v4
BS2	Not assessed	No data were identified showing this variant in unaffected individuals under the PALB2 BS2 point-based framework, so BS2 cannot be evaluated.	cspec
BS3	N/A	The PALB2 specification does not apply BS3 for this variant type in this framework. No applicable benign functional study rule was identified.	cspec
BS4	Not assessed	No quantitative segregation data were identified showing lack of segregation for this variant, so BS4 cannot be evaluated.	cspec
BP1	Met	This variant is a missense substitution, and the PALB2 specification applies BP1_Supporting to all missense variants because pathogenic PALB2 disease is predominantly associated with truncating variants and true pathogenic missense variants are thought to be exceedingly rare.	cspec
BP2	N/A	The PALB2 specification does not use BP2 in this framework.	cspec
BP3	N/A	BP3 is not applicable because this variant is not an in-frame insertion or deletion in a repetitive region, and the PALB2 specification does not use BP3 for this context.	cspec
BP4	N/A	Although SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, which is below the PALB2 BP4 splice threshold of ≤0.1, the PALB2 specification states that BP4 should not be applied for missense variants. BP4 is therefore not applied.	cspec spliceai
BP5	N/A	The PALB2 specification does not use BP5 for this gene-disease context.	cspec
BP6	N/A	BP6 is not used by this VCEP. External benign assertions without independently reviewable evidence are not applied in the PALB2 specification.	cspec
BP7	N/A	BP7 is intended for synonymous or qualifying deep intronic variants, or for RNA evidence showing no splice defect in those contexts. This variant is missense, so BP7 is not applicable.	cspec

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