NM_024675.4:c.1001A>G

PALB2 · NP_078951.2:p.(Tyr334Cys) · NM_024675.4

GRCh37: chr16:23646866 T>C · GRCh38: chr16:23635545 T>C

Gene: PALB2 Transcript: NM_024675.4

Final call

VUS

BP1 supporting

Variant details

Gene

PALB2

Transcript

NM_024675.4

Protein

NP_078951.2:p.(Tyr334Cys)

gnomAD AF

7.50003409106405e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

PALB2 VCEP BP1_Supporting is applied as this is a missense variant; true pathogenic missense variants in PALB2 are thought to be exceedingly rare.

This variant is present in gnomAD v4.1 at an allele frequency of 0.000075 (121/1,613,326 alleles), which exceeds the VCEP PM2 threshold of 0.00000333 but does not meet BS1 (>0.01%) or BA1 (>0.1%) benign population thresholds.

The variant has been observed in multiple cohorts at frequencies comparable to population controls (Balia 2010: 1/95 cases and 1/50 controls; Catucci 2012: 1/96 cases; Hellebrand 2011: 1/818 cases classified as polymorphism).

In silico predictors REVEL (0.014) and BayesDel (-0.648) are consistent with a benign interpretation, though PALB2 VCEP does not apply PP3/BP4 for missense variants as published predictors have not achieved functional outcome prediction.

No pathogenic criteria are met. With only BP1_Supporting (benign supporting) applied, the overall classification under PALB2 VCEP v1.2.0 is Uncertain Significance (VUS).

Final determination: No criteria-combination rule matched the adjudicated criteria in the Richards et.al., 2015 - Combining rules v1.2.0 framework, so the variant remains a Variant of Uncertain Significance pending human review.

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	Missense variant (p.Tyr334Cys); the PALB2 VCEP PVS1 decision tree applies only to null variants (nonsense, frameshift, canonical splice). Missense changes are not eligible for PVS1.	cspec pvs1_variant_assessment
PS1	N/A	PALB2 VCEP PS1 rule applies to splicing variants only (PS1 Splicing table). VCEP explicitly states: 'Missense: Do not use. Missense changes are not yet confirmed as a mechanism of disease for PALB2.'	cspec
PS2	N/A	PALB2 VCEP explicitly designates PS2 as Not Applicable. Informative de novo occurrences have not been observed for PALB2-associated autosomal dominant disease.	cspec
PS3	N/A	PALB2 VCEP explicitly designates PS3 as Not Applicable. Well-established functional studies for PALB2 missense variants are not available.	cspec
PS4	Not met	No case-control study demonstrates significant statistical enrichment of this variant in affected individuals. The variant has been observed at comparable frequencies in cases and controls (Balia 2010: 1/95 cases and 1/50 controls, 0.5%). VCEP PS4 requires p≤0.05 AND (OR≥3 or lower 95% CI ≥1.5).	PMID:20852946 PMID:21618343 PMID:22692731 PMID:33134171 cspec
PS5	N/A	PS5 is not defined in the PALB2 VCEP v1.2.0 criteria set. In ClinGen VCEP frameworks, PS5 is typically subsumed by other pathogenic criteria or not independently applied.	cspec
PM1	N/A	PALB2 VCEP: 'Do not use: Missense pathogenic variation in PALB2 is not yet confirmed as a mechanism of disease.' PM1 is explicitly not applicable.	cspec
PM2	Not met	gnomAD v4.1 allele frequency (7.50e-05, 0.0075%) exceeds the PALB2 VCEP PM2_Supporting threshold of ≤1/300,000 (0.000333%). The variant is approximately 22-fold more common than the VCEP-defined cutoff. Although VCEP uses PM2 as Supporting strength only, the frequency threshold is not met.	gnomad_v4 cspec
PM5	N/A	PALB2 VCEP: 'Do not use for missense changes: Missense changes are not yet confirmed as a mechanism of disease for PALB2.' PM5 under VCEP applies only to frameshifting/truncating variants upstream of p.Tyr1183 or splice variants with NMD-prone PVS1 RNA evidence.	cspec pm5_candidates
PM6	N/A	PALB2 VCEP explicitly designates PM6 as Not Applicable. Informative de novo occurrences have not been observed for PALB2-associated conditions.	cspec
PP1	Not met	No co-segregation data available meeting VCEP thresholds (LOD≥0.3 or LR≥2:1 for AD). The variant was identified by Garcia 2020 (PMID:33134171) in patient ID85, but co-segregation analysis was not performed for this family; only LOH was evaluated.	PMID:33134171 cspec
PP2	N/A	PALB2 VCEP: 'Do not use. Missense is not yet confirmed or refuted as a mechanism of disease for PALB2.'	cspec
PP3	N/A	PALB2 VCEP PP3 rule: 'Missense: Do not use.' Published in silico predictors have not achieved functional outcome prediction for PALB2 missense variants. SpliceAI delta = 0.00, confirming absence of predicted splice impact, but PP3 is not applied for missense per VCEP.	cspec spliceai
PP4	N/A	PALB2 VCEP: 'Do not use for AD disorder as breast cancer is a disease with multiple genetic etiology.' PP4 is explicitly Not Applicable.	cspec
PP5	N/A	PALB2 VCEP: Not Applicable for this VCEP, as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.	cspec
BA1	Not met	gnomAD v4.1 grpmax filtering allele frequency (6.725e-05, 0.006725%) does not exceed the PALB2 VCEP BA1 threshold of >0.1%.	gnomad_v4 cspec
BS1	Not met	gnomAD v4.1 grpmax filtering allele frequency (6.725e-05, 0.006725%) does not exceed the PALB2 VCEP BS1 threshold of >0.01%.	gnomad_v4 cspec
BS2	Not assessed	VCEP BS2 requires Fanconi Anemia proband point-table assessment (≥4 points for Strong, 2 for Moderate, 1 for Supporting). No FA-affected probands with this variant were identified in the available evidence.	cspec
BS3	N/A	PALB2 VCEP explicitly designates BS3 as Not Applicable.	cspec
BS4	Not assessed	VCEP BS4 requires quantitative co-segregation analysis with LOD or Bayes Factor values. No such analysis has been performed for this variant.	cspec
BP1	Met	PALB2 VCEP BP1 applies to all missense variants. Based on published and unpublished functional studies, PALB2 has a low rate of missense variants that are non-functional, and true pathogenic missense variants are thought to be exceedingly rare.	cspec
BP2	N/A	PALB2 VCEP explicitly designates BP2 as Not Applicable.	cspec
BP3	N/A	VCEP states BP3 is Not Applicable; small in-frame losses are neither confirmed nor refuted as a mechanism of pathogenicity for PALB2, and this is a substitution variant.
BP4	N/A	PALB2 VCEP BP4 rule: 'Missense: Do not use.' Published in silico predictors have not achieved functional outcome prediction for PALB2 missense variants. SpliceAI delta=0.00 confirms no predicted splice impact, but BP4 is explicitly not applicable for missense.	cspec spliceai
BP5	N/A	PALB2 VCEP: 'Do not use: Cases with multiple pathogenic variants have been observed with no noticeable difference in phenotype... PALB2 has moderate penetrance and will naturally occur with other pathogenic variants more frequently.'	cspec
BP6	N/A	PALB2 VCEP: Not Applicable for this VCEP, as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.	cspec
BP7	N/A	PALB2 VCEP applies BP7 to synonymous and deep intronic variants (beyond +7 donor and -21 acceptor). This is a missense variant (p.Tyr334Cys) and is not eligible for BP7 under VCEP rules.	cspec

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