NM_024675.4:c.1351T>G

PALB2 · NP_078951.2:p.(Leu451Val) · NM_024675.4

GRCh37: chr16:23646516 A>C · GRCh38: chr16:23635195 A>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.(Leu451Val)

gnomAD AF

3.0977514042107114e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

This variant is a missense change (NM_024675.4:c.1351T>G, p.Leu451Val) in PALB2, a gene where loss of function is a known disease mechanism for PALB2-related cancer predisposition (autosomal dominant) and Fanconi anemia type FA-N (autosomal recessive).

In gnomAD v4.1, the variant is present at extremely low frequency (AF = 0.00031%, 5/1,614,074 alleles; grpmax FAF = 7.9e-07), meeting the PALB2 VCEP PM2_Supporting threshold (≤0.000333%).

BP1_Supporting is applied per PALB2 VCEP rule: all missense variants in PALB2 receive BP1 because missense pathogenic variation is not yet confirmed as a disease mechanism and true pathogenic missense variants are thought to be exceedingly rare.

SpliceAI predicts no splicing impact (max delta = 0.00), and REVEL (0.027) and BayesDel (-0.741) scores are consistent with a benign in silico profile, though PP3 and BP4 are not applied to missense variants per VCEP rules.

The variant has been observed in COSMIC in 2 somatic cancer samples but has no curated functional evidence from OncoKB.

ClinVar reports this variant as Uncertain significance (VariationID 951843, 2 clinical laboratories, criteria provided single submitter) with no expert panel classification.

No published literature specifically mentions NM_024675.4:c.1351T>G; all 16 PMIDs retrieved through ClinVar and literature searches were reviewed and none contain variant-specific evidence. All available full-text papers (PMID:34242744, 15604628, 17508274, 18163131) were confirmed to not mention this variant.

No co-segregation data, case-control studies, de novo reports, or functional studies are available for this variant. PS4, PP1, BS2, BS4, and PVS1 remain not assessed due to absence of evidence.

The only criteria met are PM2_Supporting (low population frequency) and BP1_Supporting (missense in PALB2). This yields a net of one pathogenic supporting and one benign supporting criterion — insufficient for classification beyond VUS per ACMG/AMP combination rules. The variant remains Uncertain significance.

Final determination: Rule31 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 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	Not met	PVS1 is not applicable to this missense variant (p.Leu451Val) per the PALB2 VCEP v1.2.0 PVS1 Decision Tree. SpliceAI predicts no splicing impact (max delta = 0.00), and no experimental evidence of a null effect (aberrant splicing or RNA defect) has been identified for this variant.	spliceai cspec pvs1_generic_framework
PS1	N/A	PALB2 VCEP v1.2.0 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 v1.2.0 marks PS2 as not applicable: 'Do not use for AD or AR disease: Informative de novo occurrences have not yet been observed.'	cspec
PS3	N/A	PALB2 VCEP v1.2.0 marks PS3 as not applicable; functional evidence for missense variants is directed to RNA-based PVS1 assessment rather than PS3.	cspec
PS4	Not met	No case-control study or cohort analysis demonstrating statistically increased prevalence of NM_024675.4:c.1351T>G in affected individuals has been identified. PALB2 VCEP PS4 requires a case-control study with p≤0.05 and OR≥3 or lower 95% CI ≥1.5.	cspec clinvar
PS5	N/A	PS5 is not a criterion in the PALB2 VCEP v1.2.0 framework. The VCEP does not recognize PS5 as a valid criterion.	cspec
PM1	N/A	PALB2 VCEP v1.2.0 explicitly states: 'Do not use: Missense pathogenic variation in PALB2 is not yet confirmed as a mechanism of disease.'	cspec
PM2	Met	The variant is present at extremely low frequency in gnomAD v4.1 (AF = 0.00031%, 5/1,614,074 alleles), which is at or below the PALB2 VCEP PM2_Supporting threshold of ≤0.000333% (≤1/300,000). Applied as PM2_Supporting per VCEP guidance.	gnomad_v4 cspec
PM5	N/A	PALB2 VCEP v1.2.0 PM5 applies only to 'frameshifting or truncating variants with premature termination codons upstream of p.Tyr1183' and explicitly states 'Do not use for missense changes.' This variant is a missense (p.Leu451Val).	cspec
PM6	N/A	PALB2 VCEP v1.2.0 marks PM6 as not applicable: 'Do not use for AD or AR disease: Informative de novo occurrences have not yet been observed.'	cspec
PP1	Not met	No co-segregation data are available for this variant. PALB2 VCEP PP1 requires LOD score or Bayes Factor from quantitative co-segregation analysis; no family studies with this variant have been identified in the literature.	cspec
PP2	N/A	PALB2 VCEP v1.2.0 explicitly states: 'Do not use. Missense is not yet confirmed or refuted as a mechanism of disease for PALB2.'	cspec
PP3	N/A	PALB2 VCEP v1.2.0 PP3 rule states: 'Missense: Do not use.' The criterion is reserved for splicing variants with SpliceAI ≥0.2. This is a missense variant with SpliceAI max delta of 0.00.	cspec spliceai
PP4	N/A	PALB2 VCEP v1.2.0 marks PP4 as not applicable: 'Do not use for AD disorder as breast cancer is a disease with multiple genetic etiology (genetic heterogeneity).'	cspec
PP5	N/A	PALB2 VCEP v1.2.0 marks PP5 as 'Not Applicable for this VCEP' per ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation.	cspec
BA1	Not met	gnomAD v4.1 grpmax filtering allele frequency is 7.9e-07 (0.000079%), far below the PALB2 VCEP BA1 threshold of >0.1%. The variant is too rare to qualify as a common polymorphism.	gnomad_v4 cspec
BS1	Not met	gnomAD v4.1 grpmax filtering allele frequency is 7.9e-07 (0.000079%), far below the PALB2 VCEP BS1 threshold of >0.01%. The variant frequency does not exceed expectation for disorder.	gnomad_v4 cspec
BS2	Not met	No evidence of the variant observed in healthy adult individuals for a recessive (Fanconi anemia) disorder context. PALB2 VCEP BS2 requires Fanconi Anemia BS2 table-based point assignment; no qualifying proband data are available.	cspec
BS3	N/A	PALB2 VCEP v1.2.0 marks BS3 as not applicable. Functional studies are directed to RNA-based PVS1/BP7 assessment rather than BS3.	cspec
BS4	Not met	No segregation data demonstrating lack of co-segregation of this variant with disease in affected family members are available. PALB2 VCEP BS4 requires quantitative co-segregation analysis with LOD or Bayes Factor thresholds.	cspec
BP1	Met	PALB2 VCEP v1.2.0 BP1 rule states: 'Apply to all missense variants.' This variant is a missense change (p.Leu451Val) in PALB2, a gene where primarily truncating variants are known to cause disease and missense pathogenic variants are thought to be exceedingly rare.	cspec
BP2	N/A	PALB2 VCEP v1.2.0 marks BP2 as not applicable.	cspec
BP3	N/A	Trivially not applicable: variant is a substitution, not an in-frame deletion/insertion.
BP4	N/A	PALB2 VCEP v1.2.0 BP4 rule states: 'Missense: Do not use.' The criterion is reserved for splicing variants with SpliceAI ≤0.1. This is a missense variant.	cspec spliceai
BP5	N/A	PALB2 VCEP v1.2.0 marks BP5 as not applicable: 'Do not use: Cases with multiple pathogenic variants have been observed with no noticeable difference in phenotype.'	cspec
BP6	N/A	PALB2 VCEP v1.2.0 marks BP6 as 'Not Applicable for this VCEP' per ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation.	cspec
BP7	N/A	PALB2 VCEP v1.2.0 BP7 is reserved for synonymous and deep intronic variants (further than +7 donor and -21 acceptor). This variant is a missense change (p.Leu451Val) and does not qualify.	cspec

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