Classification rationale

PVS1PM5 Likely Pathogenic

PALB2 c.2488del frameshift · exon 5

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.

PVS1 + PM5 → Likely Pathogenic

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

Gene diagram · NM_024675.4 · variants mapped to exon structure

PALB2 NM_024675.4

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 8 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 2

Strength Supporting Moderate Strong Very strong

PVS1 very strong Pathogenic

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.

Case variant assessment: NM_024675.4:c.2488del; NP_078951.2:p.(Glu830SerfsTer21) / p.(E830Sfs*21); frameshift in exon 5; canonical splice consensus false.PALB2_PVS1_v1.3.pdf, page 1: the VCEP PVS1 definition includes null frameshift variants in a gene where loss of function is a known disease mechanism.PALB2_PVS1_v1.3.pdf, page 3: the VCEP considers NM_024675.3 the clinically relevant reference transcript, with 13 coding exons and a 1186-amino-acid protein; the case uses the corresponding NM_024675.4 annotation.

cspec ↗vcep_palb2_pvs1_v1_3 ↗

PM5 supporting Pathogenic

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.

Variant assessment identifies NM_024675.4:c.2488del as a frameshift with protein consequence NP_078951.2:p.(E830Sfs*21), exon 5.p.(E830Sfs*21) terminates after residue 850, which is upstream of the VCEP cutoff p.His1184.The VCEP PM5 DNA-variant rule requires an NMD-prone truncating variant receiving PVS1 at VeryStrong with a premature termination codon upstream of p.His1184.

cspec ↗

Assessed · not applied · 3 not met · 5 not assessed

Pathogenic

PS4 Not assessed: the available study reports PALB2 truncating variants collectively (OR 4.69, p=6.9×10−6), not this specific c.2488del variant.

PM2 Not met: gnomAD v4.1 South Asian AF is 0.0098799%, exceeding the PALB2 VCEP PM2 threshold of 0.000333%.

PM3 Not assessed: the governing PM3 table has no entry for c.2488del and no case-specific phase or affected-proband point assignment is available.

PP1 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.

Benign

BA1 Not met: gnomAD v4.1 grpmax FAF is 0.005136%, below the PALB2 VCEP BA1 threshold of >0.1%.

BS1 Not met: gnomAD v4.1 grpmax FAF is 0.005136%, below the PALB2 VCEP BS1 threshold of >0.01%.

BS2 Not assessed: gnomAD cannot support BS2 under the VCEP rule, and no qualifying healthy-adult clinical or research observation was available.

BS4 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.

N/A · 18 PS1 · PS2 · PS3 · PM1 · PM4 · PM6 · PP2 · PP3 · PP4 · PP5 · BS3 · BP1 · BP2 · BP3 · BP4 · BP5 · BP6 · BP7

Research & evidence

Population frequency · supports pathogenic

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 5.5758e-06; MAF= 0.00056%, 9/1614118 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 9.8799e-05; MAF= 0.00988%, 9/91094 alleles, homozygotes = 0); grpmax FAF= 5.136e-05.

v2.1

This variant is present in gnomAD v2.1 (AF= 3.9794e-06; MAF= 0.00040%, 1/251294 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 3.26627e-05; MAF= 0.00327%, 1/30616 alleles, homozygotes = 0).

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.00056% · 9 / 1,614,118
0 hom · FAF 0.0051%

South Asian

9 / 91,094

0.0099%

+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American, European (non-Finnish))

gnomAD v2.1

0.0004% · 1 / 251,294
0 hom

South Asian

1 / 30,616

0.0033%

+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals)

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Pathogenic (12 clinical laboratories) and as pathogenic (1 clinical laboratory) and as Likely pathogenic (1 clinical laboratory). (ClinVarID = 230859)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04).

SpliceAI ↗

Functional Likely Oncogenic

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

9Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 8 PMIDs not cited in assessment

18053174 ↗ Identification of a novel truncating PALB2 mutation and analysis of its contribution to early-onset breast cancer in French-Canadian women. ONCOKB

25529982 ↗ A novel PALB2 truncating mutation in an Italian family with male breast cancer. ONCOKB

28279176 ↗ PALB2 mutations in BRCA1/2-mutation negative breast and ovarian cancer patients from Poland. ONCOKB

28779002 ↗ Rare, protein-truncating variants in ATM, CHEK2 and PALB2, but not XRCC2, are associated with increased breast cancer risks. ONCOKB

28858227 ↗ The Role of PALB2 in the DNA Damage Response and Cancer Predisposition. ONCOKB

17200671 ↗ Biallelic mutations in PALB2 cause Fanconi anemia subtype FA-N and predispose to childhood cancer. CLINVAR

23918944 ↗ Tamoxifen and risk of contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. CLINVAR

25099575 ↗ Breast-cancer risk in families with mutations in PALB2. CLINVAR

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