NM_024675.4:c.194C>T

PALB2 · NP_078951.2:p.(Pro65Leu) · NM_024675.4

GRCh37: chr16:23649188 G>A · GRCh38: chr16:23637867 G>A

Gene: PALB2 Transcript: NM_024675.4

Final call

VUS

BP1 supporting

Variant details

Gene

PALB2

Transcript

NM_024675.4

Protein

NP_078951.2:p.(Pro65Leu)

gnomAD AF

5.768307553753803e-05 (v4.1)

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

The PALB2 NM_024675.4:c.194C>T (NP_078951.2:p.(Pro65Leu), p.(P65L)) variant has been reported in ClinVar, but no expert panel classification is available.

This variant is present in gnomAD v4.1 at 0.00577% (93/1612258 alleles) with a highest observed population frequency of 0.00961%, which is below the PALB2 BS1 threshold of 0.01% and above the PM2_Supporting threshold of 0.000333%.

SpliceAI predicts no significant splice impact (max delta score 0.00), and missense predictor scores are low (REVEL 0.029; BayesDel -0.55193), although the PALB2 expert specification does not use missense computational predictors for PP3 or BP4 in this setting.

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
BS4	Not assessed	No quantitative segregation or lack-of-segregation data were identified for this variant, so the PALB2 BS4 thresholds based on LOD score or likelihood ratio cannot be evaluated.	cspec PMID:25356972
PM4	N/A	This is a missense variant, and the PALB2 specification restricts PM4 to stop-loss variants rather than missense changes.	cspec
PM3	Not assessed	No evidence was identified that this variant was observed in trans with a pathogenic PALB2 variant in individuals with Fanconi anemia, so PM3 points cannot be assigned.	cspec
BP6	N/A	BP6 is not used in the PALB2 expert specification.	cspec
BP5	N/A	BP5 is not used in the PALB2 expert specification.	cspec
BP1	Met	This variant is a missense change, and the PALB2 expert specification applies BP1 to all missense variants because pathogenic missense variation is thought to be very uncommon in this gene.	cspec
BS3	N/A	BS3 is not used in the PALB2 expert specification for this context.	cspec
BS2	Not assessed	No qualifying observations were identified in healthy adults or other point-based PALB2 BS2 evidence, so BS2 cannot be assigned.	cspec
BS1	Not met	The highest observed gnomAD v4.1 population frequency is 0.00961%, which is below the PALB2 BS1 threshold of greater than 0.01%, so BS1 is not met.	cspec gnomad_v4
PP4	N/A	PP4 is not used in the PALB2 expert specification because the associated cancer phenotypes are genetically heterogeneous and not sufficiently specific for this rule.	cspec
PM6	N/A	PM6 is not used in the PALB2 expert specification.	cspec
PM2	Not met	This variant is present in gnomAD v4.1 at 0.00577%, which is above the PALB2 PM2_Supporting threshold of 0.000333%, so PM2 is not met.	cspec gnomad_v4
PM1	N/A	PM1 is not used in the PALB2 expert specification because pathogenic missense variation is not established as a disease mechanism for PALB2.	cspec hotspots
PS4	Not assessed	The variant has been reported in clinical databases and publications, but the available evidence does not provide a qualifying variant-specific case-control estimate with p-value ≤0.05 and odds ratio, hazard ratio, or relative risk ≥3, or lower 95% confidence interval ≥1.5, so PS4 cannot be assigned.	cspec clinvar PMID:20301425 PMID:20582465 PMID:25356972 PMID:28779002
BA1	Not met	The highest observed gnomAD v4.1 population frequency is 0.00961%, which is below the PALB2 BA1 threshold of greater than 0.1%, so BA1 is not met.	cspec gnomad_v4
PP1	Not assessed	No quantitative co-segregation data were identified for this variant, so the PALB2 PP1 thresholds cannot be evaluated.	cspec PMID:25356972
PVS1	Not met	PALB2 loss of function is an established disease mechanism, but this variant is a missense substitution and does not fall into the generic null-variant categories for PVS1. It is not a nonsense, frameshift, or canonical ±1,2 splice-site variant, and no RNA evidence showing a qualifying loss-of-function splice effect was identified.	cspec pvs1_gene_context pvs1_variant_assessment spliceai
BP7	N/A	BP7 is intended for synonymous and qualifying deep intronic variants, whereas this variant is a missense substitution.	cspec
BP4	N/A	SpliceAI predicts no significant splice impact for this variant (max delta score 0.00), and missense predictor scores are low (REVEL 0.029; BayesDel -0.55193); however, the PALB2 expert specification states that BP4 should not be applied for missense variants.	cspec spliceai revel bayesdel
BP2	N/A	BP2 is not used in the PALB2 expert specification.	cspec
PP2	N/A	PP2 is not used in the PALB2 expert specification because missense variation is not established as a common disease mechanism for PALB2.	cspec
PS3	N/A	PS3 is not used in the PALB2 expert specification for this context.	cspec oncokb
BP3	N/A	BP3 is not used in the PALB2 expert specification.	cspec
PP5	N/A	PP5 is not used in the PALB2 expert specification.	cspec clinvar
PP3	Not met	SpliceAI predicts no significant splice impact for this variant (max delta score 0.00), which is below the PALB2 PP3 threshold of 0.2 for splice-based use. REVEL is 0.029 and BayesDel is -0.55193, but the PALB2 expert specification does not use missense computational predictors for PP3.	cspec spliceai revel bayesdel
PM5	N/A	The PALB2 PM5 rule is repurposed for truncating or qualifying splice variants upstream of p.Tyr1183 and is not used for missense changes. This missense variant is therefore not eligible for PM5.	cspec pm5_candidates
PS2	N/A	PS2 is not used in the PALB2 expert specification.	cspec
PS1	N/A	This is a missense variant, and the PALB2 expert specification states that PS1 should not be used for missense changes. No qualifying splice-based PS1 evidence was identified.	cspec spliceai

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