NM_024675.4:c.1049_1050insT

PALB2 · NP_078951.2:p.(Gln350HisfsTer11) · NM_024675.4

GRCh37: chr16:23646817 T>TA · GRCh38: chr16:23635496 T>TA

Gene: PALB2 Transcript: NM_024675.4

Final call

Pathogenic

PVS1 very strong PM2 supporting PM5 supporting

Variant details

Gene

PALB2

Transcript

NM_024675.4

Protein

NP_078951.2:p.(Gln350HisfsTer11)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

Pathogenic: PVS1 very strong applies to the early PALB2 frameshift truncation near residue 360.

Pathogenic: PM2 supporting applies because the variant is absent from evaluated gnomAD datasets.

Pathogenic: PM5 supporting applies because the premature stop is upstream of p.His1184 under the PALB2 VCEP truncation rule.

Final determination: PALB2 VCEP Version 1.3 Rule4 classifies a variant as Pathogenic when one very-strong pathogenic criterion and at least two supporting pathogenic criteria are met; here these are PVS1, PM2, and PM5.

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	Met	Met, very strong: the early frameshift p.(Q350Hfs*11) truncates PALB2 near residue 360, far upstream of the VCEP p.His1184 cutoff.	cspec pvs1_generic_framework
PS1	N/A	Not applicable: the PALB2 PS1 specification is for matched splice-altering events, whereas this variant is a p.Gln350HisfsTer11 frameshift.	cspec vcep_palb2_ps1_1_3
PS2	N/A	Not applicable: the PALB2 VCEP explicitly excludes PS2 because informative de novo occurrences have not been established for either relevant disease context.	cspec
PS3	N/A	Not applicable: the PALB2 VCEP specification version 1.3 explicitly designates PS3 as not applicable.	cspec
PS4	Not assessed	Not assessed: group-level PALB2 truncating-variant enrichment was OR 4.69, but no exact-variant case-control statistic is available for c.1049_1050insT.	cspec PMID:28779002
PM1	N/A	Not applicable: the PALB2 VCEP explicitly marks PM1 not applicable, and no authoritative PALB2 domain table entry is present for residue 350.	cspec
PM2	Met	Met at supporting strength: the variant is absent from gnomAD v2.1, v4.1, and non-cancer subsets, giving observed frequency 0 versus the PALB2 threshold of 0.000333%.	cspec gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: no affected-proband observation or confirmed phase with a pathogenic PALB2 variant is documented for c.1049_1050insT.	cspec
PM4	N/A	Not applicable: the PALB2 VCEP explicitly designates PM4 as not applicable, and this variant is a truncating frameshift evaluated under PVS1.	cspec
PM5	Met	Met, supporting: p.Gln350HisfsTer11 creates a premature stop near His360, upstream of the PALB2 VCEP cutoff p.His1184 and within its PVS1-Very Strong truncation rule.	cspec vcep_palb2_pvs1_v1_3 pvs1_gene_context pvs1_variant_assessment
PM6	N/A	Not applicable: the PALB2 VCEP explicitly excludes PM6 because assumed de novo occurrences are not informative for either relevant disease context.	cspec
PP1	Not assessed	Not assessed: no affected-relative segregation data, meioses, LOD score, or likelihood ratio are available to compare with the PP1 threshold of LOD ≥0.3 or LR ≥2:1.	cspec
PP2	N/A	Not applicable: the PALB2 VCEP marks PP2 not applicable, and this variant is a frameshift rather than a missense substitution.	cspec
PP3	N/A	Not applicable: this frameshift variant is outside PP3's calibrated missense/splicing scope, regardless of any available predictor score.	cspec
PP4	N/A	Not applicable: the PALB2 VCEP excludes PP4 for heterogeneous autosomal-dominant breast cancer and directs recessive phenotype evidence to PM3.	cspec
PP5	N/A	Not applicable: the PALB2 VCEP prohibits PP5, and ClinVar has no exact-variant expert-panel pathogenic or likely pathogenic classification.	cspec clinvar
BA1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, so its frequency is not greater than the PALB2 VCEP BA1 threshold of 0.1%.	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, so its frequency does not exceed the PALB2 VCEP BS1 threshold of 0.01%.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: no homozygote, unaffected-carrier, phenotype, or PALB2 VCEP BS2 point data are available for this absent variant.	vcep_palb2_pm3_bs2_1_3 gnomad_v2 gnomad_v4
BS3	N/A	Not applicable: the PALB2 VCEP specification version 1.3 explicitly designates BS3 as not applicable.	cspec
BS4	Not assessed	Not assessed: no affected non-carriers, non-segregation observations, LOD score, or likelihood ratio are available to compare with the BS4 threshold of LOD ≤−0.32 or LR ≤0.48.	cspec
BP1	N/A	Not applicable: the PALB2 BP1 rule applies to missense variants, while this variant is a p.Gln350HisfsTer11 frameshift.	cspec
BP2	N/A	Not applicable: the PALB2 VCEP explicitly excludes BP2 and provides no strength assignment for this criterion.	cspec
BP3	N/A	Not applicable: the PALB2 VCEP explicitly designates BP3 as not applicable, and this variant is a protein-truncating frameshift rather than a benign repeat-region indel.	cspec
BP4	N/A	Not applicable: this frameshift variant is outside BP4's calibrated missense/splicing scope, regardless of any available predictor score.	cspec
BP5	N/A	Not applicable: the PALB2 VCEP prohibits BP5 because co-occurring pathogenic variants are expected and do not reliably explain the phenotype.	cspec
BP6	N/A	Not applicable: the PALB2 VCEP prohibits BP6, and ClinVar has no exact-variant expert-panel benign or likely benign classification.	cspec clinvar
BP7	N/A	Not applicable: this frameshift variant is not synonymous, so BP7 cannot be applied.	cspec

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