NM_024675.3:c.2027T>C

PALB2 · NP_078951.2:p.(Ile676Thr) · NM_024675.3

GRCh37: chr16:23641448 A>G · GRCh38: chr16:23630127 A>G

Gene: PALB2 Transcript: NM_024675.3

Final call

Benign

BP6 supporting benign BP1 supporting BS1 strong BA1 stand-alone benign

Variant details

Gene

PALB2

Transcript

NM_024675.3

Protein

NP_078951.2:p.(Ile676Thr)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

The PALB2 c.2027T>C (p.Ile676Thr) variant has been reported in ClinVar as Benign, including a reviewed expert panel classification.

This variant is present in gnomAD v4.1 with an overall allele frequency of 0.01425% (230/1614160) and a highest observed population frequency of 0.37653% (226/60022 alleles in the Admixed American population), which is above the PALB2 BA1 threshold of 0.1% and the BS1 threshold of 0.01%.

In silico data do not support a splice effect, with a SpliceAI maximum delta score of 0.02; REVEL is 0.003 and BayesDel is -0.705338, but the PALB2 VCEP does not use PP3 or BP4 for missense variants.

Final determination: Rule17 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 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
BS4	Not assessed	No quantitative non-segregation data were identified for this variant. The PALB2 VCEP requires LOD score or likelihood ratio evidence, and no family-based data meeting the BS4 thresholds were available.	cspec
PM4	N/A	This is a missense variant, not a stop-loss variant. The PALB2 VCEP does not use PM4 for missense changes.	cspec
PM3	Not assessed	No evidence was identified that this variant was observed in trans with a pathogenic PALB2 variant in a proband with Fanconi anemia or other data meeting the PALB2 PM3 point-based framework.	cspec
BP6	Met	Expert panel ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen classified as Benign.	cspec clinvar
BP5	N/A	BP5 is not used for PALB2 in this VCEP framework.	cspec
BP1	Met	This variant is a missense change, and the PALB2 VCEP applies BP1_Supporting to all missense variants because pathogenic PALB2 variation is predominantly truncating and true pathogenic missense variants are considered very rare.	cspec
BS3	N/A	The PALB2 VCEP does not use BS3 for protein functional studies in this framework, and no qualifying RNA evidence showing a normal transcript was identified to support an RNA-based benign code instead.	cspec
BS2	Not assessed	No qualifying observations were identified in healthy adults that could be scored under the PALB2 BS2 point-based framework. Population database counts alone are not sufficient for BS2 in this specification.	cspec
BS1	Met	Population frequency is above the PALB2 BS1 threshold. In gnomAD v4.1, the highest observed population frequency is 0.37653% (226/60022 alleles in Admixed American), which is above the BS1 threshold of 0.01%.	gnomad_v4 cspec
PP4	N/A	PP4 is not used for autosomal dominant PALB2-related cancer predisposition because the phenotype is not sufficiently specific for this gene under the PALB2 VCEP framework.	cspec
PM6	N/A	PM6 is not used for PALB2 in this VCEP framework.	cspec
PM2	Not met	Population frequency is above the PALB2 PM2_Supporting threshold. In gnomAD v4.1, the overall allele frequency is 0.01425% (230/1614160), and the highest observed population frequency is 0.37653% (226/60022 in Admixed American), both above the PM2 threshold of 0.000333%.	gnomad_v4 cspec
PM1	N/A	PM1 is not used for PALB2 because missense pathogenic variation is not an established disease mechanism in this gene-specific framework.	cspec
PS4	Not assessed	No case-control study or other quantitative enrichment data were identified showing that this variant is significantly more common in affected individuals than in controls. Available evidence does not support applying PS4 at this time.	cspec clinvar
BA1	Met	Population frequency is above the PALB2 BA1 threshold. In gnomAD v4.1, the highest observed population frequency is 0.37653% (226/60022 alleles in Admixed American), which is above the BA1 threshold of 0.1%.	gnomad_v4 cspec
PP1	Not assessed	No segregation data were identified for this variant. The PALB2 VCEP requires quantitative segregation evidence, and no LOD score or likelihood ratio meeting PP1 thresholds was available.	cspec
PVS1	Not met	This variant is a missense substitution and does not fall within the PALB2 or generic PVS1 null-variant categories. Available evidence does not show a predicted loss-of-function consequence, and the generic PVS1 scaffold states that this variant is not a nonsense, frameshift, or canonical ±1,2 splice variant.	pvs1_gene_context pvs1_variant_assessment cspec
BP7	N/A	This is not a synonymous or deep intronic variant, and no RNA study showing a normal transcript was identified. BP7 is therefore not applicable.	cspec
BP4	N/A	SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.02, which is below the PALB2 BP4 splicing threshold of 0.1. However, the PALB2 VCEP does not apply BP4 to missense variants, so BP4 is not used here. REVEL is 0.003 and BayesDel is -0.705338, but these missense predictor results are not used to apply BP4 under the PALB2 missense rule.	spliceai revel bayesdel cspec
BP2	N/A	BP2 is not used for PALB2 in this VCEP framework.	cspec
PP2	N/A	PP2 is not used for PALB2 because missense variation is not an established pathogenic mechanism in this gene-specific framework.	cspec
PS3	N/A	PS3 is not used for PALB2 protein functional studies in this framework, and no qualifying RNA evidence establishing a damaging splice effect was identified to support an RNA-based loss-of-function code instead.	cspec
BP3	N/A	This is not an in-frame insertion or deletion in a repetitive region, and BP3 is not used for PALB2 in this VCEP framework.	cspec
PP5	N/A	PP5 is not used by this VCEP.	cspec
PP3	N/A	SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.02, which is below the PALB2 PP3 splicing threshold of 0.2. In addition, the PALB2 VCEP does not apply PP3 to missense variants. REVEL is 0.003 and BayesDel is -0.705338, but these missense predictor results are not used to apply PP3 under the PALB2 missense rule.	spliceai revel bayesdel cspec
PM5	N/A	This variant is a missense change, and the PALB2 VCEP does not use PM5 for missense variants. The PALB2 PM5 adaptation is limited to qualifying truncating or splice variants expected to behave as loss-of-function alleles.	cspec
PS2	N/A	PS2 is not used for PALB2 in this VCEP framework.	cspec
PS1	N/A	This variant is a missense change, and the PALB2 VCEP does not use PS1 for missense variants. No evidence was identified that this substitution matches a qualifying PALB2 splice-based PS1 table entry.	cspec spliceai

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