NM_024675.3:c.2734T>G

PALB2 · NP_078951.2:p.(Trp912Gly) · NM_024675.3

GRCh37: chr16:23637571 A>C · GRCh38: chr16:23626250 A>C

Gene: PALB2 Transcript: NM_024675.3

Final call

PM2 supporting BP1 supporting

Variant details

Gene

PALB2

Transcript

NM_024675.3

Protein

NP_078951.2:p.(Trp912Gly)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

The PALB2 c.2734T>G (p.Trp912Gly) variant has not been observed in COSMIC and has been reported in ClinVar as Uncertain Significance, including expert-panel review.

This variant is absent from gnomAD v2.1 and gnomAD v4.1, placing its observed population frequency below the PALB2 PM2_Supporting threshold of 0.000333%.

SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.03, and although REVEL and BayesDel scores are available, the PALB2 expert-panel specification does not use missense computational predictors for PP3 or BP4.

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	This missense variant does not fall into the PALB2 loss-of-function variant categories used for PVS1, and SpliceAI does not support a splice-disrupting effect (max delta score 0.03). Available evidence therefore does not support applying PVS1.	cspec pvs1_gene_context pvs1_variant_assessment spliceai
PS1	N/A	Under the PALB2 specification, PS1 is not used for missense changes and is reserved for specific splicing-table scenarios. No PALB2 splicing-table evidence was identified for this variant.	cspec spliceai
PS2	N/A	The PALB2 specification does not use PS2 for this disease context. No qualifying confirmed de novo evidence was identified.	cspec
PS3	N/A	The PALB2 specification does not use PS3 for protein functional assays, and no RNA evidence was identified that would redirect assessment to a splice-based framework. Available evidence therefore does not support PS3 use in this framework.	cspec spliceai
PS4	Not met	This variant has been reported in ClinVar, but no case-control study showing significant enrichment in affected individuals was identified. The available evidence does not meet the PALB2 PS4 requirement of p-value less than or equal to 0.05 with an odds ratio, hazard ratio, or relative risk at least 3 or lower 95% confidence interval at least 1.5.	cspec clinvar
PM1	N/A	The PALB2 specification does not use PM1 because missense pathogenicity and hotspot/domain-based missense interpretation are not established mechanisms for this gene in this framework.	cspec
PM2	Met	This variant is absent from gnomAD v4.1 and gnomAD v2.1. Its observed population frequency is therefore below the PALB2 PM2_Supporting threshold of 1 in 300,000 (0.000333%), supporting PM2 at supporting strength.	cspec gnomad_v4 gnomad_v2
PM3	Not met	No evidence was identified that this variant was observed in trans with a pathogenic PALB2 variant in a proband meeting the PALB2 Fanconi anemia scoring framework. Available evidence does not support PM3.	cspec
PM4	N/A	PM4 is not applicable because this variant is a missense substitution, not a stop-loss variant or qualifying in-frame length-change variant under the PALB2 specification.	cspec
PM5	N/A	Under the PALB2 specification, PM5 is not used for missense changes and instead applies only as PM5_Supporting for qualifying truncating or splice variants upstream of p.Tyr1183*. This missense variant does not meet that rule.	cspec pm5_candidates
PM6	N/A	The PALB2 specification does not use PM6 in this disease context. No assumed de novo evidence relevant to a PALB2 PM6 framework was identified.	cspec
PP1	Not met	No segregation data were identified for this variant. Available evidence does not show the quantitative co-segregation required to reach the PALB2 PP1 thresholds.	cspec
PP2	N/A	The PALB2 specification does not use PP2 because missense variation is not an established pathogenic mechanism in this framework.	cspec
PP3	Not met	SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.03, which is below the PALB2 PP3 splicing threshold of 0.2. REVEL (0.562) and BayesDel (0.00991955) are available, but the PALB2 specification does not use missense computational predictors for PP3. Available computational evidence therefore does not support PP3.	cspec spliceai revel bayesdel
PP4	N/A	The PALB2 specification does not use PP4 for the autosomal dominant cancer-predisposition setting because the phenotype is not sufficiently specific to a single genetic cause.	cspec
PP5	N/A	PP5 is not used in this PALB2 expert-panel framework.	cspec
BA1	Not met	This variant is absent from gnomAD v4.1 and therefore is below the PALB2 BA1 threshold of greater than 0.1% filtering allele frequency. BA1 is not met.	cspec gnomad_v4
BS1	Not met	This variant is absent from gnomAD v4.1 and therefore is below the PALB2 BS1 threshold of greater than 0.01% filtering allele frequency. BS1 is not met.	cspec gnomad_v4
BS2	Not met	No evidence was identified that this variant was observed in healthy adults in a configuration that meets the PALB2 BS2 point-based framework. Available evidence does not support BS2.	cspec
BS3	N/A	The PALB2 specification does not use BS3 for protein functional assays, and no RNA evidence was identified to support a splice-based benign RNA code. Available evidence therefore does not support BS3 use in this framework.	cspec spliceai
BS4	Not met	No non-segregation data were identified for this variant. Available evidence does not show the quantitative lack of segregation required to reach the PALB2 BS4 thresholds.	cspec
BP1	Met	This variant is a missense substitution, and the PALB2 expert-panel specification applies BP1 to all missense variants because truncating variants are the predominant established disease mechanism and true pathogenic missense variants are thought to be very rare. BP1 is met at supporting strength.	cspec
BP2	N/A	The PALB2 specification does not use BP2 in this framework.	cspec
BP3	N/A	BP3 is not applicable because this variant is not an in-frame insertion or deletion in a repetitive region without known function.	cspec
BP4	N/A	SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.03, which is below the PALB2 BP4 splicing threshold of 0.1. However, the PALB2 specification states that BP4 should not be applied for missense variants. REVEL (0.562) and BayesDel (0.00991955) are available, but the PALB2 framework does not use missense computational predictors for BP4.	cspec spliceai revel bayesdel
BP5	N/A	BP5 is not used in the PALB2 specification.	cspec
BP6	N/A	BP6 is not used in this PALB2 expert-panel framework.	cspec
BP7	N/A	BP7 is intended for synonymous or deep intronic variants, or for RNA studies showing no aberrant splicing in those settings. This variant is a missense substitution and no RNA study showing normal splicing was identified.	cspec spliceai

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.