NM_024675.4:c.1049_1051delinsTTCT

PALB2 · NP_078951.2:p.(Gln350LeufsTer11) · NM_024675.4

GRCh37: chr16:23646816 TTT>AGAA · GRCh38: chr16:23635495 TTT>AGAA

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.(Gln350LeufsTer11)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

Pathogenic: PVS1 very strong because the Q350 frameshift creates an early premature stop expected to trigger nonsense-mediated decay.

Pathogenic: PM2 supporting because the variant is absent from gnomAD v2.1 and v4.1.

Pathogenic: PM5 supporting because the PALB2 VCEP recognizes qualifying NMD-prone truncations upstream of p.His1184.

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.

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: frameshift p.(Q350Lfs*11) creates a premature stop 11 codons after Gln350 in coding exon 4, well upstream of p.His1184.	cspec vcep_palb2_pvs1_v1_3 pvs1_generic_framework
PS1	N/A	Not applicable: the PALB2 PS1 specification is for matched splicing effects, whereas this variant is a Q350 frameshift.	cspec vcep_palb2_ps1_1_3
PS2	N/A	Not applicable: PALB2 VCEP version 1.3 explicitly designates PS2 as not applicable.	cspec
PS3	N/A	Not applicable: PALB2 VCEP Version 1.3 excludes PS3, and no validated assay directly tested c.1049_1051delinsTTCT or p.(Gln350LeufsTer11).	cspec
PS4	Not assessed	Not assessed: aggregate PALB2 truncating variants had OR 4.69, but the study did not report this exact variant.	cspec PMID:28779002
PM1	N/A	Not applicable: the PALB2 VCEP marks PM1 not applicable, and the variant is a Q350 truncating frameshift rather than a missense domain change.	cspec
PM2	Met	Met at supporting strength: the variant is absent from gnomAD v2.1 and v4.1, giving observed frequency 0 versus the PALB2 PM2 threshold of <=0.000333%.	cspec gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: no affected Fanconi-anemia proband or documented second pathogenic PALB2 allele with confirmed trans phase is available for the VCEP's 1–8-point PM3 framework.	cspec vcep_palb2_pm3_bs2_1_3 PMID:28858227 PMID:28279176
PM4	N/A	Not applicable: PALB2 VCEP PM4 is restricted to stop-loss variants, whereas this variant is a frameshift producing p.(Q350Lfs*11).	cspec
PM5	Met	Met, supporting: PALB2 PM5 applies to NMD-prone PVS1-very-strong truncations upstream of His1184, and this Q350 frameshift terminates near residue 360.	cspec vcep_palb2_pvs1_v1_3 pvs1_variant_assessment
PM6	N/A	Not applicable: PALB2 VCEP version 1.3 explicitly designates PM6 as not applicable.	cspec
PP1	Not assessed	Not assessed: no affected-relative segregation data, meioses, LOD, or Bayes factor were available to meet 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 truncating frameshift rather than missense.	cspec
PP3	N/A	Not applicable: this is a frameshift variant, whereas PALB2 PP3 is specified for qualifying splice-impact variants rather than truncating variants.	cspec
PP4	N/A	Not applicable: the PALB2 VCEP prohibits PP4 for hereditary breast cancer because its phenotype is genetically heterogeneous.	cspec
PP5	N/A	Not applicable: the PALB2 VCEP prohibits PP5, and ClinVar has no exact-variant expert-panel classification.	cspec clinvar
BA1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, rather than exceeding the PALB2 VCEP BA1 threshold of >0.1% group-maximum filtering allele frequency.	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, rather than exceeding the PALB2 VCEP BS1 threshold of >0.01% group-maximum filtering allele frequency.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: the PALB2 VCEP excludes population cohorts such as gnomAD for BS2, and no qualifying healthy-adult or homozygote observation is available.	cspec gnomad_v2 gnomad_v4
BS3	N/A	Not applicable: PALB2 VCEP Version 1.3 excludes BS3, and no validated benign assay result exists for c.1049_1051delinsTTCT or p.(Gln350LeufsTer11).	cspec
BS4	Not assessed	Not assessed: no affected relatives tested negative and no quantitative non-segregation result met the BS4 supporting threshold of LOD ≤−0.32 or LR ≤0.48.	cspec
BP1	N/A	Not applicable: PALB2 BP1 is limited to missense variants, while this variant is a Q350 frameshift.	cspec
BP2	N/A	Not applicable: the governing PALB2 VCEP specification explicitly designates BP2 as not applicable.	cspec vcep_palb2_pm3_bs2_1_3
BP3	N/A	Not applicable: PALB2 VCEP marks BP3 unavailable, and this variant is a frameshift rather than an in-frame repeat-region length change.	cspec
BP4	N/A	Not applicable: this is a frameshift variant, outside the PALB2 BP4 scope for absence of predicted splicing impact.	cspec
BP5	N/A	Not applicable: the PALB2 VCEP prohibits BP5 because co-occurring pathogenic variants do not reliably explain phenotype differences.	cspec
BP6	N/A	Not applicable: the PALB2 VCEP prohibits BP6, and ClinVar has no exact-variant expert-panel classification.	cspec clinvar
BP7	N/A	Not applicable: this is a frameshift variant, not a synonymous or qualifying deep intronic variant eligible for PALB2 BP7.	cspec

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