NM_024675.4:c.1960A>G

PALB2 · NP_078951.2:p.(Ile654Val) · NM_024675.4

GRCh37: chr16:23641515 T>C · GRCh38: chr16:23630194 T>C

Gene: PALB2 Transcript: NM_024675.4

Final call

VUS

BP1 supporting

Variant details

Gene

PALB2

Transcript

NM_024675.4

Protein

NP_078951.2:p.(Ile654Val)

gnomAD AF

4.336674637887667e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

The PALB2 c.1960A>G (p.Ile654Val) variant has been reported in ClinVar with predominantly uncertain significance submissions and one likely benign submission, and no expert panel classification was identified.

This variant is present in gnomAD v4 at 0.00043% overall (7/1,614,140 alleles) with a highest observed population frequency of 0.00769% in South Asians, which is above the PALB2 PM2_Supporting threshold of 0.000333% and below the BS1 threshold of 0.01%.

Under the PALB2 expert specification, BP1 is met because this is a missense variant in a gene for which established pathogenic variation is predominantly truncating.

SpliceAI predicts no significant splice impact for this variant (maximum delta score 0.01); REVEL is 0.043 and BayesDel is -0.826097, although the PALB2 expert specification does not use PP3 or BP4 for missense prediction alone.

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 non-segregation data were identified, so the PALB2 BS4 thresholds cannot be evaluated for this variant.	cspec clinvar
PM4	N/A	This is a missense substitution, and the PALB2 expert specification does not use PM4 for this variant type.	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 cannot be assessed.	cspec clinvar
BP6	N/A	BP6 is not used in this PALB2 expert specification.	cspec
BP5	N/A	BP5 is not used in the PALB2 expert specification.	cspec
BP1	Met	This variant is a missense substitution, and the PALB2 expert specification applies BP1 to all missense variants because established pathogenic PALB2 variation is predominantly truncating.	cspec
BS3	N/A	No PALB2 protein functional assay framework supporting BS3 use was identified for this missense variant in the expert specification.	cspec oncokb
BS2	Not assessed	No qualifying observations in healthy adult individuals or other evidence meeting the PALB2 BS2 point-based framework were identified.	cspec clinvar
BS1	Not met	The highest observed gnomAD v4 population frequency is 0.00769% in South Asians, 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 for PALB2-related cancer predisposition in this expert specification because the phenotype is not sufficiently specific.	cspec
PM6	N/A	PM6 is not used in the PALB2 expert specification.	cspec
PM2	Not met	This variant is present in gnomAD v4 at 0.00043% (7/1,614,140 alleles), which is above the PALB2 PM2_Supporting threshold of 0.000333%, so PM2 is not met.	cspec gnomad_v4 gnomad_v2
PM1	N/A	PM1 is not used for PALB2 missense variants because missense pathogenic variation is not an established disease mechanism in this expert specification.	cspec hotspots
PS4	Not assessed	No qualifying case-control study showing significant enrichment of this exact variant in affected individuals was identified, so PS4 cannot be applied.	cspec clinvar
BA1	Not met	The highest observed gnomAD v4 population frequency is 0.00769%, which is well below the PALB2 BA1 threshold of greater than 0.1%, so BA1 is not met.	cspec gnomad_v4
PP1	Not assessed	No segregation data were identified for this variant, so PP1 cannot be assessed.	cspec clinvar
PVS1	Not met	This variant is a missense substitution, not a predicted loss-of-function variant, and the generic PVS1 scaffold specifically notes that it does not fall within the usual null-variant categories, so PVS1 is not met.	cspec pvs1_gene_context pvs1_variant_assessment
BP7	N/A	BP7 is intended for synonymous or deep intronic variants, and this variant is missense.	cspec
BP4	N/A	SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, but the PALB2 expert specification states BP4 should not be applied for missense variants, so BP4 is not applicable here.	cspec spliceai
BP2	N/A	BP2 is not used in this PALB2 expert specification.	cspec
PP2	N/A	PP2 is not used for PALB2 because missense variation is not an established disease mechanism in this expert specification.	cspec
PS3	N/A	PS3 is not used for this PALB2 variant under the available expert specification, and no variant-specific reviewed functional study was identified in the retrieved evidence.	cspec oncokb
BP3	N/A	BP3 is not used in this PALB2 expert specification.	cspec
PP5	N/A	PP5 is not used in this PALB2 expert specification.	cspec
PP3	N/A	SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, and the PALB2 expert specification states PP3 should not be applied for missense variants unless there is predicted splice impact, so PP3 is not applicable.	cspec spliceai revel bayesdel
PM5	N/A	The PALB2 PM5 rule is a truncation-cutoff framework and not a classic same-residue missense rule, and the PM5 candidate review marked this missense variant as not eligible for classic PM5 assessment.	cspec pm5_candidates
PS2	N/A	PS2 is not used in this PALB2 expert specification.	cspec
PS1	N/A	The PALB2 expert specification directs PS1 to a splicing table, and this variant has no predicted splice effect by SpliceAI (maximum delta score 0.01), so PS1 is not applicable on the available evidence.	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.