Variant classification summary

NM_024675.4:c.1209G>A

PALB2 · NP_078951.2:p.(Leu403=) · NM_024675.4

GRCh37: chr16:23646658 C>T · GRCh38: chr16:23635337 C>T

Gene: PALB2 Transcript: NM_024675.4

Final call

Likely Benign

BP4 supporting benign BP7 supporting benign

Variant details

Gene

PALB2

Transcript

NM_024675.4

Protein

NP_078951.2:p.(Leu403=)

gnomAD AF

4.337007811570641e-06 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_024675.4:c.1209G>A (p.Leu403=) is a synonymous variant in exon 4 of PALB2 with no predicted splicing impact (SpliceAI max delta 0.00), meeting BP7_Supporting per PALB2 VCEP v1.2.0.

2

SpliceAI predicts no splicing impact (max delta 0.00, below VCEP threshold of 0.1), meeting BP4_Supporting per PALB2 VCEP v1.2.0.

3

The variant is present in gnomAD v4.1 at a total allele frequency of 4.34×10⁻⁶ (7/1,614,016 alleles, grpmax FAF 7.9×10⁻⁷), exceeding the VCEP PM2_Supporting threshold of 3.33×10⁻⁶; PM2 is not met.

4

ClinVar reports this variant as Likely benign (6 clinical laboratories) and Benign (1 clinical laboratory); no expert panel has classified it as pathogenic (VariationID: 185784).

5

No published literature was identified that directly references NM_024675.4:c.1209G>A. Eight papers retrieved from ClinVar and OncoKB sources were reviewed; none mention the specific variant.

Final determination: Rule19 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 Likely Benign.

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	NM_024675.4:c.1209G>A is a synonymous variant (p.Leu403=) and does not fall into any PVS1 null-variant bucket (nonsense, frameshift, or canonical ±1,2 splice consensus). The PALB2 VCEP PVS1 Decision Tree is designed for truncating and splice-altering variants.	pvs1_gene_context pvs1_variant_assessment spliceai
PS1	N/A	Per PALB2 VCEP v1.2.0, PS1 is not used for missense variants and is applied only to splicing variants via the PALB2 PS1 Splicing table. This synonymous variant has no splice impact (SpliceAI max delta 0.00) and is neither missense nor splicing-altering.	cspec spliceai
PS2	N/A	VCEP specifies PS2 is not applicable for PALB2; de novo occurrences are not yet observed for autosomal dominant PALB2-related disease.	cspec
PS3	N/A	VCEP specifies PS3 is not applicable for PALB2; functional protein assays are not validated for PALB2 missense assessment.	cspec
PS4	Not met	No case-control study data are available for NM_024675.4:c.1209G>A. PS4 requires a study with p≤0.05 and OR≥3 (or lower 95% CI≥1.5). This variant is reported in ClinVar as Likely benign/Benign by 7 clinical laboratories but lacks the controlled epidemiological data required.	clinvar cspec
PS5	Not met	No reputable source has reported NM_024675.4:c.1209G>A as pathogenic. ClinVar reports Likely benign (6 clinical labs) and Benign (1 clinical lab). No expert panel has classified this variant as pathogenic.	clinvar
PM1	N/A	VCEP specifies PM1 is not applicable for PALB2; missense pathogenic variation is not yet confirmed as a mechanism of disease.	cspec
PM2	Not met	The gnomAD v4.1 total allele frequency is 4.34×10⁻⁶ (7/1,614,016 alleles), which exceeds the PALB2 VCEP PM2_Supporting threshold of ≤3.33×10⁻⁶ (≤0.000333%, 1/300,000). PM2 is not met.	gnomad_v4 cspec
PM5	N/A	Per PALB2 VCEP v1.2.0, PM5 applies only to frameshifting or truncating variants with premature termination codons upstream of p.Tyr1183, or to splice variants. This is a synonymous variant and does not meet either criterion. PM5 is additionally not used for missense changes per VCEP.	cspec pm5_candidates
PM6	N/A	VCEP specifies PM6 is not applicable for PALB2; informative de novo occurrences have not yet been observed for autosomal dominant PALB2-related disease.	cspec
PP1	Not met	No co-segregation data are available for NM_024675.4:c.1209G>A. Per VCEP, quantitative co-segregation analysis is required; no LOD score or affected-relative data have been provided.	cspec
PP2	N/A	VCEP specifies PP2 is not applicable for PALB2; missense is not yet confirmed or refuted as a mechanism of disease.	cspec
PP3	Not met	Per VCEP, PP3 is not used for missense variants and requires SpliceAI ≥0.2 for splicing assessment. This synonymous variant has SpliceAI max delta 0.00, well below the threshold. No pathogenic in silico signal is present.	spliceai cspec
PP4	N/A	VCEP specifies PP4 is not applicable for PALB2 autosomal dominant disease; breast cancer has multiple genetic etiologies and no features reliably distinguish hereditary from sporadic cases.	cspec
PP5	N/A	VCEP specifies PP5 is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.	cspec
BA1	Not met	The gnomAD v4.1 grpmax filtering allele frequency is 7.9×10⁻⁷ (0.000079%), far below the PALB2 VCEP BA1 threshold of >0.1%. BA1 is not met.	gnomad_v4 cspec
BS1	Not met	The gnomAD v4.1 grpmax filtering allele frequency is 7.9×10⁻⁷ (0.000079%), below the PALB2 VCEP BS1 threshold of >0.01%. BS1 is not met.	gnomad_v4 cspec
BS2	Not met	No proband-level data are available for BS2 assessment. Per VCEP, BS2 requires counting affected probands using Fanconi Anemia BS2 tables; no individual-level phenotype or genotype data have been provided to calculate BS2 points.	cspec
BS3	N/A	VCEP specifies BS3 is not applicable for PALB2; for RNA, use BP7(RNA) instead. For protein, assays are not validated for PALB2 missense assessment.	cspec
BS4	Not met	No co-segregation data are available to calculate a LOD score or Bayes Factor for lack of segregation. Per VCEP, quantitative co-segregation analysis is required; no such data have been provided.	cspec
BP1	Not met	Per VCEP, BP1 applies to all missense variants in PALB2 (low rate of functional missense variants). NM_024675.4:c.1209G>A is a synonymous variant (p.Leu403=), not a missense variant. BP1 does not apply.	cspec
BP2	N/A	VCEP specifies BP2 is not applicable for PALB2; use ATM PM3/BP2 table instead.	cspec
BP4	Met	SpliceAI predicts no splicing impact for this synonymous variant (max delta score = 0.00, ≤0.1 VCEP threshold). Per PALB2 VCEP v1.2.0, BP4_Supporting may be applied for splicing assessment when SpliceAI ≤0.1.	spliceai cspec
BP5	N/A	VCEP specifies BP5 is not applicable for PALB2; cases with multiple pathogenic variants have been observed without noticeable phenotype differences, and PALB2's moderate penetrance leads to frequent co-occurrence with other pathogenic variants.	cspec
BP6	N/A	VCEP specifies BP6 is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.	cspec
BP7	Met	NM_024675.4:c.1209G>A is a synonymous variant (p.Leu403=) located in exon 4 at position c.1209, far from splice donor (475 nt from +1) and acceptor (997 nt from -1) sites. SpliceAI predicts no splicing impact (max delta = 0.00). Per PALB2 VCEP v1.2.0, BP7_Supporting applies to synonymous variants beyond ±7/21 of splice consensus sites.	spliceai cspec

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