NM_024675.4:c.1050_1051delinsTCT

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

GRCh37: chr16:23646816 TT>AGA · GRCh38: chr16:23635495 TT>AGA

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

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

Pathogenic: the early p.(Gln350HisfsTer11) frameshift supports PVS1 at very strong strength through PALB2 loss of function.

Pathogenic: absence from gnomAD v2.1 and v4.1 meets PALB2's PM2 supporting rarity threshold.

Pathogenic: the observed truncation ends at codon 360, upstream of the PALB2 VCEP PM5 cutoff at p.His1184.

Final determination: PALB2 VCEP Version 1.3 Rule4 classifies a variant as Pathogenic when one Pathogenic Very Strong criterion and at least two Pathogenic Supporting 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 at very strong: frameshift p.(Q350Hfs*11) in exon 4 truncates PALB2 after 349 native residues and is far upstream of the extreme 3-prime region.	cspec pvs1_generic_framework PMID:18446436
PS1	N/A	Not applicable: the variant is a p.Gln350HisfsTer11 frameshift, whereas PALB2 PS1 is restricted to matched splicing events in the VCEP table.	cspec
PS2	N/A	Not applicable: the PALB2 VCEP explicitly excludes PS2 because informative de novo occurrences have not been established for this autosomal dominant cancer-predisposition condition.	cspec
PS3	N/A	Not applicable: the PALB2 VCEP specification designates PS3 as unavailable for PALB2 variant classification.	cspec
PS4	Not met	Not met: the exact variant occurred in 1/360 cases versus 0/864 controls, with two-sided exact p=1.0 rather than the VCEP PS4 threshold of ≤.05.	cspec PMID:18446436
PM1	N/A	Not applicable: the governing PALB2 VCEP explicitly marks PM1 as not applicable, and this variant is a truncating frameshift rather than missense.	cspec
PM2	Met	Met at supporting strength: the variant is absent from gnomAD v2.1 and v4.1, satisfying PALB2's ≤0.000333% PM2 threshold.	cspec gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: PALB2 PM3 is restricted to recessive Fanconi anemia with biallelic evidence, but this variant is reported heterozygously without a pathogenic variant in trans.	cspec vcep_palb2_pm3_bs2_1_3 PMID:18446436
PM4	N/A	Not applicable: the PALB2 VCEP Version 1.3 specification explicitly designates PM4 as not applicable.	cspec
PM5	Met	Met at supporting: the observed p.Gln350HisfsTer11 frameshift terminates at codon 360, upstream of the PALB2 VCEP PM5 cutoff p.His1184.	cspec PMID:18446436
PM6	N/A	Not applicable: the PALB2 VCEP explicitly excludes PM6 for both autosomal dominant and recessive disease in its Version 1.3 framework.	cspec
PP1	Not assessed	Not assessed: one affected mother segregated the variant with the proband, but no required quantitative result was provided to compare with LOD ≥0.3 or LR ≥2:1.	cspec PMID:18446436
PP2	N/A	Not applicable: PALB2 VCEP excludes PP2, and the variant is a p.Gln350HisfsTer11 frameshift rather than a missense variant.	cspec
PP3	N/A	Not applicable: this is a frameshift variant, outside the PALB2 VCEP PP3 scope for missense, silent, and qualifying intronic/splicing variants.	cspec
PP4	N/A	Not applicable: the PALB2 VCEP excludes PP4 for autosomal dominant disease because breast cancer is genetically heterogeneous and not phenotype-specific.	cspec
PP5	N/A	Not applicable: the exact ClinVar record has no expert-panel assertion, only one non-expert Pathogenic submission without assertion criteria.	cspec clinvar
BA1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, so no allele frequency exceeds PALB2's >0.1% BA1 threshold.	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, so no allele frequency exceeds PALB2's >0.01% BS1 threshold.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: no documented homozygote or unaffected-carrier observations are available to meet PALB2's BS2 point thresholds.	cspec gnomad_v2 gnomad_v4
BS3	N/A	Not applicable: the PALB2 VCEP specification designates BS3 as unavailable for PALB2 variant classification.	cspec
BS4	Not assessed	Not assessed: no non-segregation was reported, and no quantitative LOD or LR was provided to compare with the BS4 thresholds.	cspec PMID:18446436
BP1	N/A	Not applicable: BP1 is restricted to missense variants, while this variant produces the p.Gln350HisfsTer11 frameshift.	cspec
BP2	N/A	Not applicable: the PALB2 VCEP excludes BP2, and the case reports no pathogenic variant in cis or in trans with this heterozygous frameshift.	cspec vcep_palb2_pm3_bs2_1_3 PMID:18446436
BP3	N/A	Not applicable: BP3 is explicitly not applicable in PALB2 VCEP Version 1.3 and this variant is a truncating frameshift, not an in-frame repeat-region indel.	cspec
BP4	N/A	Not applicable: this is a frameshift variant, outside the PALB2 VCEP BP4 scope for predicted splice impact in qualifying splicing variants.	cspec
BP5	N/A	Not applicable: the PALB2 VCEP explicitly excludes BP5 because PALB2 moderate penetrance and multiple pathogenic variants make co-occurrence non-informative.	cspec
BP6	N/A	Not applicable: the exact ClinVar record has no benign expert-panel classification and instead has one non-expert Pathogenic submission without criteria.	cspec clinvar
BP7	N/A	Not applicable: this is a frameshift variant, not a synonymous or qualifying deep intronic variant covered by the PALB2 VCEP BP7 rule.	cspec

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