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.1 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 BA1.2 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.3 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.4
Final classification
Uncertain Significance - Conflicting Evidence
PM2BP1
PALB2
c.1432T>C
p.Ser478Pro
This variant
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.
Richards et.al., 2015 - Combining rules v1.2.0 criteria-combination framework: matched Rule31 (Benign.Supporting >=1 + Pathogenic.Supporting >=1) with applied criteria: PM2 supporting, BP1 supporting; maps to Uncertain Significance - Conflicting Evidence.
Classification rationale
PM2
BP1
Uncertain Significance - Conflicting Evidence
PALB2 c.1432T>C
PM2 + BP1
→
Uncertain Significance - Conflicting Evidence
4
cspec ↗pvs1_gene_contextpvs1_variant_assessment
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 · 2 applied · 8 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 · 2
Strength
Supporting
Moderate
Strong
Very strong
PM2
supporting
Pathogenic
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.
gnomAD v4.1 absentgnomAD v2.1 absent
BP1
supporting
Benign
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.
Variant protein change p.(Ser478Pro) is missensePALB2 BP1 applies to all missense variants
Assessed · not applied
· 3 not met · 5 not assessed
Pathogenic
PVS1
This missense variant does not fall into the PALB2 loss-of-function categories used for PVS1.
PS4
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.
PM3
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.
PP1
No segregation data were identified for this variant, so the PALB2 quantitative co-segregation thresholds for PP1 were not met or evaluated.
Benign
BA1
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%.
BS1
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%.
BS2
No data were identified showing this variant in unaffected individuals under the PALB2 BS2 point-based framework, so BS2 cannot be evaluated.
BS4
No quantitative segregation data were identified showing lack of segregation for this variant, so BS4 cannot be evaluated.
N/A · 18
PS1 · PS2 · PS3 · PM1 · PM4 · PM5 · PM6 · PP2 · PP3 · PP4 · PP5 · BS3 · BP2 · BP3 · BP4 · BP5 · BP6 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories) and as Likely benign (1 clinical laboratory).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
Functional
Unknown Oncogenic Effect
OncoKB has not reviewed this specific variant; no variant-level oncogenicity or biological effect is available. Gene-level context: PALB2, a scaffolding protein involved in DNA repair, is altered in various cancers.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links