NM_024675.4:c.2234A>G

PALB2 · NP_078951.2:p.(Lys745Arg) · NM_024675.4

GRCh37: chr16:23641241 T>C · GRCh38: chr16:23629920 T>C

Gene: PALB2 Transcript: NM_024675.4

Final call

Likely Benign

BP1_Supporting BS1_Strong

Variant details

Gene

PALB2

Transcript

NM_024675.4

Protein

NP_078951.2:p.(Lys745Arg)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

The PALB2 c.2234A>G (p.Lys745Arg, p.K745R) variant has been reported in ClinVar with conflicting interpretations, including uncertain significance and likely benign submissions.

In population data, this variant is present in gnomAD v4.1 at 13/1,614,018 alleles overall (0.00081%) with a highest observed African/African American frequency of 12/74,906 alleles (0.01602%), which is above the PALB2 BS1 threshold of 0.01% and above the PM2_Supporting threshold of 0.000333%.

Under the PALB2 specification, BP1 applies because this is a missense variant in a gene where truncating variants are the predominant established disease mechanism.

SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.02; however, PP3 and BP4 are not applied to missense variants in the PALB2 framework.

Final determination: Rule18 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 Likely 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 segregation or lack-of-segregation data were identified, so BS4 cannot be assessed for this variant.	cspec
PM4	N/A	This is a missense substitution and not a stop-loss variant, so PM4 is not applicable under the PALB2 specification.	cspec
PM3	Not assessed	No Fanconi anemia proband or confirmed in-trans data were identified, so PM3 cannot be assessed.	cspec
BP6	N/A	BP6 is not used by this VCEP.	cspec
BP5	N/A	BP5 is not applicable under the PALB2 specification.	cspec
BP1	Met	This variant is a missense change, and the PALB2 specification applies BP1 to all missense variants because truncating variants are the predominant established disease mechanism for PALB2.	cspec
BS3	N/A	BS3 is not applicable under the PALB2 specification for this review context.	cspec
BS2	Not assessed	No qualifying observations in unaffected adults or Fanconi-anemia-specific BS2 point data were identified, so BS2 cannot be assessed.	cspec
BS1	Met	This variant is present in gnomAD v4.1 with a highest observed African/African American allele frequency of 0.01602% (12/74,906), which is above the PALB2 BS1 threshold of 0.01%, supporting BS1.	cspec gnomad_v4
PP4	N/A	PP4 is not applicable for PALB2 hereditary breast, ovarian, and pancreatic cancer because the phenotype is not sufficiently specific for a single genetic etiology.	cspec
PM6	N/A	PM6 is not applicable under the PALB2 specification.	cspec
PM2	Not met	This variant is present in gnomAD v4.1 at 0.00081% (13/1,614,018 alleles), 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 applicable under the PALB2 specification because missense pathogenicity in PALB2 is not an established mechanism for using hotspot or critical-domain evidence.	cspec
PS4	Not assessed	ClinVar shows conflicting laboratory classifications, but no qualifying PALB2 case-control study with p-value 0.05 or less and odds ratio, hazard ratio, or relative risk of at least 3 was identified, so PS4 cannot be assessed.	cspec clinvar
BA1	Not met	The highest observed gnomAD v4.1 allele frequency is 0.01602% (12/74,906), which is below the PALB2 BA1 threshold of 0.1%, so BA1 is not met.	cspec gnomad_v4
PP1	Not assessed	No informative co-segregation data were identified, so PP1 cannot be assessed.	cspec
PVS1	N/A	Loss of function is an established PALB2 disease mechanism, but this variant is a missense substitution outside the PVS1 null-variant categories, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.02, so PVS1 is not applicable.	cspec pvs1_gene_context pvs1_variant_assessment spliceai
BP7	N/A	This variant is missense rather than synonymous or deep intronic, so BP7 is not applicable.	cspec
BP4	N/A	SpliceAI predicts no significant splice impact with a maximum delta score of 0.02, but the PALB2 specification does not apply BP4 to missense variants, so BP4 is not applicable.	cspec spliceai
BP2	N/A	BP2 is not applicable under the PALB2 specification.	cspec
PP2	N/A	PP2 is not applicable because missense pathogenicity is not an established PALB2 mechanism for this rule.	cspec
PS3	N/A	PS3 is not applicable under the PALB2 specification for this review context.	cspec
BP3	N/A	This is not an in-frame insertion or deletion in a repetitive region, and BP3 is not applicable under the PALB2 specification.	cspec
PP5	N/A	PP5 is not used by this VCEP.	cspec
PP3	N/A	SpliceAI does not predict a splice effect for this variant, with a maximum delta score of 0.02, and the PALB2 specification does not apply PP3 to missense variants, so PP3 is not applicable.	cspec spliceai
PM5	N/A	PM5 is not applicable because the PALB2 specification does not use PM5 for missense changes.	cspec
PS2	N/A	PS2 is not applicable under the PALB2 specification.	cspec
PS1	N/A	PS1 is not applicable because the PALB2 specification does not use PS1 for missense changes and reserves it for qualifying splicing-table evidence.	cspec

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.