NM_024675.4:c.1096A>G

PALB2 · NP_078951.2:p.(Asn366Asp) · NM_024675.4

GRCh37: chr16:23646771 T>C · GRCh38: chr16:23635450 T>C

Gene: PALB2 Transcript: NM_024675.4

Final call

PM2 supporting BP1 supporting benign

Variant details

Gene

PALB2

Transcript

NM_024675.4

Protein

NP_078951.2:p.(Asn366Asp)

gnomAD AF

4.956162740559749e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_024675.4:c.1096A>G (p.Asn366Asp) is a missense variant in PALB2 with an extremely low population frequency in gnomAD v4.1 (total AF = 4.96e-06, 8/1,614,152 alleles, 0 homozygotes), meeting PM2_Supporting under the PALB2 VCEP threshold of ≤ 0.000333%.

Under the PALB2 HBOP VCEP v1.2, BP1 is applied at supporting benign level to all PALB2 missense variants. Missense pathogenic variation in PALB2 is not yet confirmed as a mechanism of disease, and true missense pathogenic variants are thought to be exceedingly rare.

This variant has been reported in ClinVar as Uncertain significance by 5 clinical laboratories and Likely benign by 1 laboratory (VCV000188117), with an overall review status of 'criteria provided, single submitter.' No expert panel has reviewed this variant.

SpliceAI predicts no splicing impact (max delta = 0.00). In silico missense predictors (REVEL = 0.046, BayesDel = -0.707777) lean toward benign, but the PALB2 VCEP does not permit the use of PP3 or BP4 for missense variants.

The majority of ACMG criteria are not applicable under the PALB2 VCEP for missense variants: PVS1 (not a null variant), PS1/PS3/PM1/PP2 (missense pathogenic variation not confirmed), PS5 (not in VCEP), PM5 (truncation-only rule), PP3/BP4 (missense not used), PS2/PM6 (de novo not applicable), PP4/BP5 (not applicable per VCEP), BP7 (not synonymous), PP5/BP6 (not for use per VCEP).

With one pathogenic supporting criterion (PM2_Supporting) and one benign supporting criterion (BP1), the evidence is balanced and insufficient to classify this variant as pathogenic or benign. The variant is classified as Uncertain Significance under PALB2 VCEP v1.2 combination rules.

Final determination: Rule31 in the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PALB2 Version 1.2 v1.2 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	N/A	PVS1 applies only to null variants (nonsense, frameshift, canonical splice sites). NM_024675.4:c.1096A>G is a missense variant (p.Asn366Asp) and does not qualify for PVS1 under the PALB2 VCEP PVS1 Decision Tree.	cspec pvs1_variant_assessment
PS1	N/A	The PALB2 VCEP specifies that PS1 is not to be used for missense variants because missense pathogenic variation in PALB2 is not yet confirmed as a mechanism of disease. The PS1 Splicing table is only applicable for variants with a predicted splicing effect, and SpliceAI max delta score is 0.00 (no splicing impact).	cspec spliceai
PS2	N/A	The PALB2 VCEP marks PS2 as not applicable: informative de novo occurrences have not yet been observed for autosomal dominant PALB2-related cancer predisposition, and de novo is unlikely for this common cancer phenotype.	cspec
PS3	N/A	The PALB2 VCEP marks PS3 as not applicable for protein-level functional assays. No well-established functional studies have been validated and shown reproducible and robust performance in a clinical diagnostic laboratory setting for PALB2 missense variants.	cspec
PS4	Not met	No case-control study data are available for NM_024675.4:c.1096A>G to demonstrate significantly increased prevalence in affected individuals versus controls. The PALB2 VCEP requires a case-control study with p ≤ 0.05 and OR/RR/HR ≥ 3 or lower 95% CI ≥ 1.5.	cspec
PS5	N/A	The PALB2 VCEP does not list PS5 as a standalone criterion. Missense pathogenic variation in PALB2 is not yet confirmed as a mechanism of disease, and the VCEP delegates same-codon comparisons to the PS1 Splicing table, which is not applicable to this missense variant.	cspec
PM1	N/A	The PALB2 VCEP explicitly states: 'Do not use. Missense pathogenic variation in PALB2 is not yet confirmed as a mechanism of disease.' PM1 is not to be applied for PALB2 missense variants.	cspec
PM2	Met	This variant is extremely rare in population databases, with a total allele frequency of 4.96e-06 (0.00000050%) in gnomAD v4.1, well below the PALB2 VCEP PM2_Supporting threshold of ≤ 0.000333% (1/300,000). All 8 observed alleles are in the South Asian subpopulation (AF = 0.00878%), but the VCEP exception is for n=1 with frequency > 0.0003% and does not apply here.	gnomad_v4 cspec
PM5	N/A	The PALB2 VCEP PM5 rule applies only to frameshifting or truncating variants with premature termination codons upstream of p.Tyr1183, or splice variants with NMD-prone premature termination. This missense variant (p.Asn366Asp) does not fit either category, and the VCEP explicitly states: 'Do not use for missense changes.'	cspec pm5_candidates
PM6	N/A	The PALB2 VCEP marks PM6 as not applicable for both autosomal dominant and autosomal recessive disease: informative de novo occurrences have not been observed, and de novo AR conditions are unlikely to be informed by phase.	cspec
PP1	Not met	No co-segregation data are available for this variant. Quantitative co-segregation analysis is mandated by the PALB2 VCEP for PP1 assessment, and no LOD scores or family segregation data exist in the evidence packet.	cspec
PP2	N/A	The PALB2 VCEP explicitly states: 'Do not use. Missense is not yet confirmed or refuted as a mechanism of disease for PALB2.' PP2 is not to be applied for PALB2 missense variants.	cspec
PP3	N/A	The PALB2 VCEP PP3 rule states: 'Missense: Do not use.' The only applicable PP3 path is for splicing predictions (SpliceAI ≥ 0.2), and this variant has a SpliceAI max delta score of 0.00, indicating no predicted splicing impact. REVEL score is 0.046 and BayesDel score is -0.707777, both leaning toward benign, but in silico missense predictors are not to be used per VCEP.	cspec spliceai revel bayesdel
PP4	N/A	The PALB2 VCEP marks PP4 as not applicable for autosomal dominant disease because breast cancer has multiple genetic etiologies (genetic heterogeneity) and there are no features that can readily distinguish hereditary from sporadic causes.	cspec
PP5	N/A	The PALB2 VCEP explicitly marks PP5 as 'Not Applicable for this VCEP' as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. This criterion is not for use in PALB2 variant interpretation.	cspec
BA1	Not met	The PALB2 VCEP BA1 threshold is grpmax filtering allele frequency > 0.1% in gnomAD v4. The observed grpmax FAF is 4.368e-05 (0.00004368%), which is far below the 0.1% threshold. This variant is too rare to satisfy BA1.	gnomad_v4 cspec
BS1	Not met	The PALB2 VCEP BS1 threshold is grpmax filtering allele frequency > 0.01% in gnomAD v4. The observed grpmax FAF is 4.368e-05 (0.00004368%), which is well below the 0.01% threshold. This variant is too rare to satisfy BS1.	gnomad_v4 cspec
BS2	Not met	The PALB2 VCEP BS2 criterion requires proband-level data per the Fanconi Anemia BS2 tables. No homozygous or compound heterozygous proband data are available in the evidence packet. The 8 heterozygous observations in gnomAD v4 are from a population-based cohort and are explicitly excluded from BS2 per VCEP instructions.	cspec
BS3	N/A	The PALB2 VCEP marks BS3 as not applicable. Well-established functional studies showing no damaging effect on PALB2 protein function or splicing are not available for this missense variant.	cspec
BS4	Not met	No co-segregation data are available to demonstrate lack of segregation with disease. The PALB2 VCEP requires quantitative co-segregation analysis with LOD scores for BS4 application.	cspec
BP1	Met	The PALB2 VCEP explicitly applies BP1 at supporting level to all missense variants in PALB2. True missense pathogenic variants are thought to be exceedingly rare, and the gene has a low rate of missense variants that are non-functional in relevant assays. NM_024675.4:c.1096A>G (p.Asn366Asp) is a missense variant and therefore receives BP1.	cspec
BP2	N/A	The PALB2 VCEP marks BP2 as not applicable for this gene. Observed in trans/cis data for PALB2 should be evaluated through the ATM PM3/BP2 table which is not applicable here.	cspec
BP4	N/A	The PALB2 VCEP BP4 rule explicitly states: 'Missense: Do not use.' The splicing component of BP4 (SpliceAI ≤ 0.1 with no predicted splicing impact) is not to be applied for missense variants per the VCEP. REVEL (0.046) and BayesDel (-0.707777) are not used because published predictors have not been validated for PALB2 missense functional outcome.	cspec spliceai revel bayesdel
BP5	N/A	The PALB2 VCEP marks BP5 as not applicable. Cases with multiple pathogenic variants have been observed with no noticeable difference in phenotype, and PALB2 has moderate penetrance, making co-occurrence with other pathogenic variants more common in the population.	cspec
BP6	N/A	The PALB2 VCEP explicitly marks BP6 as 'Not Applicable for this VCEP' as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.	cspec
BP7	N/A	BP7 applies to synonymous and deep intronic variants. NM_024675.4:c.1096A>G is a missense variant (p.Asn366Asp) and does not qualify for BP7 under standard ACMG/AMP guidelines or the PALB2 VCEP.	cspec

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