NM_024675.4:c.2488del

PALB2 · NP_078951.2:p.(Glu830SerfsTer21) · NM_024675.4

GRCh37: chr16:23640986 TC>T · GRCh38: chr16:23629665 TC>T

Gene: PALB2 Transcript: NM_024675.4

Final call

Likely Pathogenic

PVS1 very strong PM5 supporting

Variant details

Gene

PALB2

Transcript

NM_024675.4

Protein

NP_078951.2:p.(Glu830SerfsTer21)

gnomAD AF

5.57580053007277e-06 (v4.1)

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

Likely Pathogenic: PVS1 very strong reflects the exon 5 frameshift truncating PALB2 before the critical WD40 domain.

Likely Pathogenic: PM5 supporting reflects the VCEP rule for this PVS1 very strong truncating variant terminating upstream of p.His1184.

Final determination: Rule19 of the PALB2 VCEP Version 1.3 framework is satisfied by one PVS1 very strong criterion and one PM5 supporting criterion, resulting in a Likely Pathogenic classification.

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.Glu830SerfsTer21 truncates PALB2 in exon 5, upstream of the critical WD40 domain and far from the 1186-residue C-terminus.	cspec vcep_palb2_pvs1_v1_3 pvs1_variant_assessment
PS1	N/A	Not applicable: c.2488del is a frameshift, whereas PALB2 PS1 addresses missense exclusions and splicing-table comparisons.	cspec vcep_palb2_ps1_1_3
PS2	N/A	Not applicable: the PALB2 VCEP explicitly marks PS2 as not applicable.	cspec
PS3	N/A	Not applicable: the PALB2 VCEP explicitly designates PS3 as not applicable, so functional assay findings cannot be assigned this criterion.	cspec
PS4	Not assessed	Not assessed: the available study reports PALB2 truncating variants collectively (OR 4.69, p=6.9×10−6), not this specific c.2488del variant.	cspec PMID:28779002
PM1	N/A	Not applicable: the PALB2 VCEP explicitly excludes PM1 because missense pathogenic variation is not an established disease mechanism.	cspec
PM2	Not met	Not met: gnomAD v4.1 South Asian AF is 0.0098799%, exceeding the PALB2 VCEP PM2 threshold of 0.000333%.	cspec gnomad_v4 gnomad_v2
PM3	Not assessed	Not assessed: the governing PM3 table has no entry for c.2488del and no case-specific phase or affected-proband point assignment is available.	vcep_palb2_pm3_bs2_1_3 PMID:17200671
PM4	N/A	Not applicable: the PALB2 VCEP explicitly designates PM4 as not applicable.	cspec
PM5	Met	Met at Supporting: the frameshift creates a stop at residue 850, upstream of His1184, and the VCEP rule requires PVS1 VeryStrong for this DNA-variant path.	cspec pvs1_variant_assessment
PM6	N/A	Not applicable: the PALB2 VCEP explicitly marks PM6 as not applicable.	cspec
PP1	Not assessed	Not assessed: no variant-specific LOD, Bayes factor, or documented affected-relative segregation is available for the VCEP's minimum LOD 0.3 or LR 2:1 threshold.	cspec
PP2	N/A	Not applicable: the VCEP excludes PP2 because missense is not an established or refuted PALB2 disease mechanism, and this variant is a frameshift.	cspec
PP3	N/A	Not applicable: PP3 names silent, missense/in-frame, and specified intronic variants, whereas c.2488del is a coding frameshift.	cspec
PP4	N/A	Not applicable: the VCEP excludes PP4 for autosomal dominant breast cancer because hereditary and sporadic disease are not readily distinguishable.	cspec
PP5	N/A	Not applicable: the PALB2 VCEP explicitly prohibits PP5 use, regardless of reputable-source pathogenic classifications.	cspec
BA1	Not met	Not met: gnomAD v4.1 grpmax FAF is 0.005136%, below the PALB2 VCEP BA1 threshold of >0.1%.	cspec gnomad_v4 gnomad_v2
BS1	Not met	Not met: gnomAD v4.1 grpmax FAF is 0.005136%, below the PALB2 VCEP BS1 threshold of >0.01%.	cspec gnomad_v4 gnomad_v2
BS2	Not assessed	Not assessed: gnomAD cannot support BS2 under the VCEP rule, and no qualifying healthy-adult clinical or research observation was available.	cspec vcep_palb2_pm3_bs2_1_3 gnomad_v4 gnomad_v2
BS3	N/A	Not applicable: the PALB2 VCEP explicitly designates BS3 as not applicable, so benign functional assay findings cannot be assigned this criterion.	cspec
BS4	Not assessed	Not assessed: no variant-specific non-segregation LOD or Bayes factor is available to meet the VCEP's Supporting threshold of LOD ≤-.32 or LR ≤.48.	cspec
BP1	N/A	Not applicable: BP1 applies to all PALB2 missense variants, but c.2488del is a frameshift.	cspec
BP2	N/A	Not applicable: the PALB2 Version 1.3 VCEP explicitly designates BP2 as not applicable.	cspec
BP3	N/A	Not applicable: the PALB2 VCEP explicitly designates BP3 as not applicable.	cspec
BP4	N/A	Not applicable: BP4 cannot be used for a coding frameshift because no predicted splice impact does not remove its truncating protein effect.	cspec
BP5	N/A	Not applicable: the PALB2 VCEP prohibits BP5 because co-occurring pathogenic variants may not alter phenotype and are expected with moderate penetrance.	cspec
BP6	N/A	Not applicable: the PALB2 VCEP explicitly prohibits BP6 use, regardless of reputable-source benign classifications.	cspec
BP7	N/A	Not applicable: BP7 is limited to synonymous or deep intronic variants, while c.2488del is a coding frameshift.	cspec

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