NM_024675.4:c.3044C>T

PALB2 · NP_078951.2:p.(Thr1015Ile) · NM_024675.4

GRCh37: chr16:23632752 G>A · GRCh38: chr16:23621431 G>A

Gene: PALB2 Transcript: NM_024675.4

Final call

VUS

BP1 supporting benign

Variant details

Gene

PALB2

Transcript

NM_024675.4

Protein

NP_078951.2:p.(Thr1015Ile)

gnomAD AF

9.9131729960211e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_024675.4:c.3044C>T (p.Thr1015Ile) is a missense variant in PALB2, a gene in which loss-of-function is an established mechanism for autosomal dominant hereditary breast, ovarian, and pancreatic cancer predisposition.

This variant is present in gnomAD v4.1 at a total allele frequency of 0.00099% (16/1,614,014 alleles; grpmax FAF 0.000803%), predominantly in the European (non-Finnish) subpopulation. It is also present in gnomAD v2.1 at 0.00119% (3/251,446 alleles) and is absent from gnomAD-Canada.

This variant has been reported in ClinVar as Uncertain significance by 6 clinical laboratories and as Likely benign by 1 laboratory (ClinVar Variation ID 141554). No expert panel classifications are available.

In silico predictors yield mixed results: REVEL score 0.238 (below the 0.5 threshold commonly used for deleterious prediction), BayesDel score -0.308 (below the 0.0 threshold for benign prediction), and SpliceAI max delta 0.00 (no predicted splicing impact).

PALB2 VCEP BP1_Supporting is met: this criterion applies to all missense variants in PALB2 because true pathogenic missense variants are thought to be exceedingly rare, per the ClinGen HBOP VCEP v1.2.0.

PALB2 VCEP PM2_Supporting is not met: the variant frequency in gnomAD v4 (0.00099%) exceeds the VCEP threshold of ≤0.000333%. BS1 and BA1 are also not met as the grpmax FAF (0.000803%) does not exceed either the BS1 (>0.01%) or BA1 (>0.1%) thresholds.

Multiple PALB2 VCEP criteria are not applicable to missense variants by explicit VCEP rule: PVS1 (not a null variant), PS1, PM1, PM5, PP2, PP3, BP4, BP7. Additionally, PS2, PS3, PM6, PP4, PP5, BP2, BP3, BP5, BP6 are not applicable per VCEP framework.

PS4, PP1, BS2, and BS4 could not be assessed due to absence of variant-specific case-control, segregation, or Fanconi Anemia proband data in the evidence reviewed.

No reviewed publication (10 PMIDs screened, 5 full-text papers read) mentioned NM_024675.4:c.3044C>T. None of the ClinVar-submitted PMIDs contained variant-specific evidence for this missense.

With only BP1_Supporting (supporting benign) met and no pathogenic criteria met, this variant is classified as Uncertain Significance (VUS) per ACMG/AMP 2015 combining rules. The single supporting benign criterion is insufficient for Likely Benign classification, which requires ≥2 supporting benign criteria or 1 strong benign + 1 supporting benign.

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	NM_024675.4:c.3044C>T is a missense variant (p.Thr1015Ile), not a null variant (nonsense, frameshift, or canonical splice site). The PALB2 VCEP PVS1 decision tree applies to truncating and splice variants, not missense substitutions.	pvs1_variant_assessment cspec
PS1	N/A	PALB2 VCEP explicitly states: 'Missense: Do not use. Missense changes are not yet confirmed as a mechanism of disease for PALB2.' The PS1 splicing table is intended for splice-altering variants only.	cspec
PS2	N/A	PALB2 VCEP marks PS2 as not applicable for both autosomal dominant and autosomal recessive disease; informative de novo occurrences have not been observed for PALB2.	cspec
PS3	N/A	PALB2 VCEP marks PS3 as not applicable; functional protein assays are not validated for PALB2 missense variant interpretation per VCEP guidance.	cspec
PS4	Not assessed	PALB2 VCEP PS4 requires case-control studies with p≤0.05 AND (OR≥3 OR lower 95% CI ≥1.5). No case-control data for NM_024675.4:c.3044C>T were identified in any reviewed publication. The BCAC study (PMID:33471991) analyzed breast cancer risk genes but did not report variant-specific odds ratios for this missense.	cspec
PS5	N/A	PS5 is not defined as a criterion in the PALB2 VCEP framework (ClinGen HBOP VCEP v1.2.0). The criterion is absent from the VCEP criteria list.	cspec
PM1	N/A	PALB2 VCEP marks PM1 as not applicable: 'Missense pathogenic variation in PALB2 is not yet confirmed as a mechanism of disease.'	cspec
PM2	Not met	PALB2 VCEP PM2_Supporting requires frequency ≤0.000333% (1/300,000) in gnomAD v4. This variant has total AF = 9.91e-06 (0.00099%, 16/1,614,014 alleles) in gnomAD v4.1, which exceeds the threshold. The variant is present in 16 alleles, predominantly in the European (non-Finnish) subpopulation.	gnomad_v4 cspec
PM5	N/A	PALB2 VCEP states: 'Do not use for missense changes: Missense changes are not yet confirmed as a mechanism of disease for PALB2.' PM5 in this VCEP applies only to frameshifting/truncating variants with premature termination codons upstream of p.Tyr1183, or splice variants with confirmed NMD-prone splicing impact.	cspec pm5_candidates
PM6	N/A	PALB2 VCEP marks PM6 as not applicable: 'Informative de novo occurrences have not yet been observed and de novo AR conditions are unlikely to be informed by phase.'	cspec
PP1	Not assessed	PALB2 VCEP PP1 requires quantitative co-segregation analysis (LOD scores or Bayes Factors for AD; affected relative counts for AR). No co-segregation data for NM_024675.4:c.3044C>T were identified in any reviewed publication.	cspec
PP2	N/A	PALB2 VCEP marks PP2 as not applicable: 'Missense is not yet confirmed or refuted as a mechanism of disease for PALB2.'	cspec
PP3	N/A	PALB2 VCEP states: 'Missense: Do not use.' While SpliceAI max delta = 0.00 (no predicted splicing impact), REVEL = 0.238, and BayesDel = -0.308, the VCEP explicitly excludes missense variants from PP3 because published predictors have not achieved reliable functional outcome prediction for PALB2 missense variants.	cspec spliceai revel bayesdel
PP4	N/A	PALB2 VCEP marks PP4 as not applicable: breast cancer has multiple genetic etiologies and no features readily distinguish hereditary from sporadic causes.	cspec
PP5	N/A	PALB2 VCEP marks PP5 as 'Not Applicable for this VCEP' per ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation.	cspec
BA1	Not met	PALB2 VCEP BA1 requires grpmax filtering AF >0.1% in gnomAD v4. This variant has grpmax FAF = 8.03e-06 (0.000803%) in gnomAD v4.1, well below the stand-alone benign threshold.	gnomad_v4 cspec
BS1	Not met	PALB2 VCEP BS1 requires grpmax filtering AF >0.01% in gnomAD v4. This variant has grpmax FAF = 8.03e-06 (0.000803%) in gnomAD v4.1, below the strong benign threshold.	gnomad_v4 cspec
BS2	Not assessed	PALB2 VCEP BS2 requires Fanconi Anemia proband data scored via the BS2 point table. No Fanconi Anemia proband data are available for NM_024675.4:c.3044C>T in the evidence reviewed. The variant is absent from COSMIC and has no reported homozygous observations.	cspec
BS3	N/A	PALB2 VCEP marks BS3 as not applicable; functional protein assays are not validated for PALB2 variant interpretation per VCEP guidance.	cspec
BS4	Not assessed	PALB2 VCEP BS4 requires quantitative co-segregation analysis (LOD scores or Bayes Factors). No segregation data for NM_024675.4:c.3044C>T were identified in any reviewed publication.	cspec
BP1	Met	PALB2 VCEP BP1 applies to all missense variants in PALB2. The VCEP states: 'Based on published and unpublished functional studies, PALB2 has a low rate of missense variants that are non-functional in relevant assays. True missense pathogenic variants are not yet confirmed or refuted but are thought to be exceedingly rare.' NM_024675.4:c.3044C>T (p.Thr1015Ile) is a missense substitution and therefore BP1_Supporting is applied per VCEP rule.	cspec
BP2	N/A	PALB2 VCEP marks BP2 as not applicable for this gene; use ATM PM3/BP2 table instead per VCEP guidance.	cspec
BP3	N/A	Skipped per instructions. PALB2 VCEP also marks BP3 as not applicable: small in-frame losses are neither confirmed nor refuted as a mechanism of pathogenicity.
BP4	N/A	PALB2 VCEP states: 'Missense: Do not use.' BP4 for splice predictions is not applicable to missense variants; SpliceAI max delta = 0.00, confirming no predicted splicing impact, but the VCEP rule excludes missense variants regardless.	cspec spliceai
BP5	N/A	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.	cspec
BP6	N/A	PALB2 VCEP marks BP6 as 'Not Applicable for this VCEP' per ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation.	cspec
BP7	N/A	BP7 applies to synonymous variants and deep intronic variants (beyond +7 donor / -21 acceptor). NM_024675.4:c.3044C>T is a missense variant (p.Thr1015Ile), not a synonymous or deep intronic substitution.	cspec

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