NM_024675.3:c.2014G>C

PALB2 · NP_078951.2:p.(Glu672Gln) · NM_024675.3

GRCh37: chr16:23641461 C>G · GRCh38: chr16:23630140 C>G

Gene: PALB2 Transcript: NM_024675.3

Final call

Benign

BA1 stand-alone benign BP1 supporting BP6 supporting benign

Variant details

Gene

PALB2

Transcript

NM_024675.3

Protein

NP_078951.2:p.(Glu672Gln)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

The PALB2 c.2014G>C (p.Glu672Gln; p.E672Q) variant has been reported in ClinVar as Benign by the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, with additional benign and likely benign clinical laboratory submissions.

This variant is common in population databases; in gnomAD v4.1 the allele frequency is 2.71302% with a grpmax filtering allele frequency of 5.70171%, and the highest observed population frequency is 15.35088% in the Amish population, which is well above the PALB2 BA1 threshold of 0.1%.

Computational data do not support a deleterious effect: SpliceAI predicts no significant splice impact with a max delta score of 0.01, REVEL is 0.029, and BayesDel is -0.736359; however, the PALB2 VCEP specification does not apply PP3 or BP4 to 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
PVS1	Not met	This variant is a missense substitution, c.2014G>C (p.Glu672Gln; p.E672Q), and does not fall into the PALB2 loss-of-function variant categories used for PVS1. Available evidence supports PALB2 loss of function as a disease mechanism, but this specific variant is not a null variant and does not meet PVS1.	cspec pvs1_gene_context pvs1_variant_assessment
PS1	N/A	PALB2 VCEP PS1 guidance is directed to the PALB2 PS1 splicing table. This missense substitution does not have evidence here supporting a same-splice-effect PS1 application.	cspec spliceai
PS2	N/A	This criterion is not applicable in the PALB2 VCEP specification for this context.	cspec
PS3	N/A	This criterion is not applicable in the PALB2 VCEP specification. No qualifying PALB2 VCEP functional framework for PS3 use was identified for this missense variant in the reviewed materials.	cspec oncokb
PS4	Not assessed	Available evidence does not identify a qualifying case-control study for this exact variant showing a significant enrichment in affected individuals at the PALB2 VCEP threshold of p≤0.05 with odds ratio, hazard ratio, or relative risk ≥3 or lower 95% confidence interval ≥1.5.	cspec clinvar PMID:18288683 PMID:18302019 PMID:19333784 PMID:20122277 PMID:21365267 PMID:21932393 PMID:22052327 PMID:22692731
PM1	N/A	This criterion is not applicable in the PALB2 VCEP specification.	cspec
PM2	Not met	This variant is far more common than the PALB2 PM2 threshold. In gnomAD v4.1, the allele frequency is 2.71302% with grpmax filtering allele frequency 5.70171%, which is well above the PM2 threshold of ≤0.000333%.	cspec gnomad_v4
PM3	Not assessed	No data were identified showing this variant in trans with a pathogenic PALB2 variant in probands meeting the Fanconi anemia point-based PM3 framework.	cspec clinvar
PM4	N/A	PALB2 VCEP does not apply PM4 to missense variants. This variant is not a stop-loss variant.	cspec
PM5	N/A	PALB2 VCEP PM5 applies to truncating or qualifying splice variants predicted to cause loss of function upstream of p.Tyr1183. This missense substitution does not meet that variant-type requirement.	cspec pvs1_variant_assessment
PM6	N/A	This criterion is not applicable in the PALB2 VCEP specification for this context.	cspec
PP1	Not assessed	No segregation data were identified that meet the PALB2 VCEP quantitative thresholds for PP1.	cspec clinvar
PP2	N/A	This criterion is not applicable in the PALB2 VCEP specification.	cspec
PP3	N/A	PALB2 VCEP does not use PP3 for missense variants. Although SpliceAI shows no predicted splice effect (max delta score 0.01), and REVEL 0.029 and BayesDel -0.736359 do not suggest a damaging effect, the PALB2 VCEP specification states that missense PP3 should not be applied.	cspec spliceai revel bayesdel
PP4	N/A	This criterion is not applicable in the PALB2 VCEP specification.	cspec
PP5	N/A	This criterion is not applicable in the PALB2 VCEP specification.	cspec
BA1	Met	This variant meets BA1. In gnomAD v4.1, the grpmax filtering allele frequency is 5.70171%, which is well above the PALB2 BA1 threshold of >0.1%; the highest observed population frequency is 15.35088% in the Amish population, and 715 homozygotes are present.	cspec gnomad_v4
BS1	Not assessed	The population frequency also exceeds the PALB2 BS1 threshold of >0.01% in gnomAD v4.1, but BA1 is already met at a much higher frequency threshold, so BS1 was not additionally counted as separate benign evidence.	cspec gnomad_v4
BS2	Not assessed	No qualifying PALB2 Fanconi anemia BS2 point-based data were identified. Although this variant is seen in many gnomAD individuals, including homozygotes, the reviewed materials do not provide the phenotyped proband-level evidence required for BS2 under the PALB2 specification.	cspec gnomad_v4 gnomad_v2
BS3	N/A	This criterion is not applicable in the PALB2 VCEP specification.	cspec oncokb
BS4	Not assessed	No quantitative non-segregation data were identified that meet the PALB2 VCEP BS4 thresholds.	cspec
BP1	Met	This variant meets BP1 because it is a missense substitution, and the PALB2 VCEP specification applies BP1 to all missense variants.	cspec
BP2	N/A	This criterion is not applicable in the PALB2 VCEP specification.	cspec
BP3	N/A	This criterion is not applicable in the PALB2 VCEP specification.	cspec
BP4	N/A	PALB2 VCEP does not use BP4 for missense variants. SpliceAI predicts no significant splice impact with a max delta score of 0.01, and REVEL 0.029 and BayesDel -0.736359 are consistent with a benign computational profile, but the PALB2 VCEP specification states that missense BP4 should not be applied.	cspec spliceai revel bayesdel
BP5	N/A	This criterion is not applicable in the PALB2 VCEP specification.	cspec
BP6	Met	Expert panel ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen classified as Benign.	cspec clinvar
BP7	N/A	BP7 is intended for synonymous and deep intronic variants, or for RNA evidence showing no aberrant splicing in those variant classes. This variant is a missense substitution and does not meet the PALB2 BP7 variant-type requirements.	cspec spliceai

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