Final classification

Pathogenic

PVS1PM2PM5

PALB2

c.1050_1051delinsTCT

p.Gln350HisfsTer11

frameshift · exon 4

Gene context NCBI Gene ↗ OncoKB ↗

PALB2 encodes a tumor suppressor protein that partners with BRCA2 (and also interacts with BRCA1) to repair double-stranded DNA breaks through the homologous recombination pathway. It acts as a scaffold that stabilizes BRCA2 in the cell nucleus and helps recruit DNA-repair machinery to sites of damage. Inherited mutations in PALB2 increase susceptibility to breast cancer, with smaller associated risks for ovarian, pancreatic, and prostate cancer and melanoma, and inheriting two mutated copies causes Fanconi anemia complementation group N. Rare somatic alterations in PALB2 are also found across various tumor types.

This variant

PALB2 is a tumor suppressor that supports BRCA1/BRCA2-mediated homologous-recombination repair, so inherited loss-of-function alleles increase susceptibility to breast cancer and other related cancers.

Transcript

NM_024675.4

HGVS · transcript:coding

NM_024675.4:c.1050_1051delinsTCT

GRCh38

chr16:23635495 TT>AGA

GRCh37

chr16:23646816 TT>AGA

Pathogenic: PVS1 (very strong), PM2 (supporting), and PM5 (supporting) satisfy Rule4 of the PALB2 VCEP Version 1.3 framework.

Classification rationale

PVS1PM2PM5 Pathogenic

PALB2 c.1050_1051delinsTCT frameshift · exon 4

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.

PVS1 + PM2 + PM5 → 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 · 3 applied · 6 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 · 3

Strength Supporting Moderate Strong Very strong

PVS1 very strong Pathogenic

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.

The PALB2 VCEP Version 1.3 PVS1 specification identifies null variants, including frameshift variants, as eligible for PVS1 when loss of function is an established disease mechanism.The case variant is NM_024675.4:c.1050_1051delinsTCT, predicted to produce p.(Gln350HisfsTer11) / p.(Q350Hfs*11), an early truncation rather than an extreme 3-prime truncation.The exact variant was reported as a heterozygous truncating frameshift in exon 4 and described as retaining only 349 residues of native PALB2 (PMID:18446436).

cspec ↗pvs1_generic_framework ↗PMID:18446436 ↗

PM2 supporting Pathogenic

Met at supporting strength: the variant is absent from gnomAD v2.1 and v4.1, satisfying PALB2's ≤0.000333% PM2 threshold.

The PALB2 Version 1.3 specification defines PM2 supporting as frequency ≤1/300,000 (0.000333%) in the gnomAD subpopulation with the highest frequency, with an exception for one carrier confined to a single subpopulation.The variant is reported absent from gnomAD v2.1 and gnomAD v4.1, which is below the specified PM2 frequency threshold.

cspec ↗gnomad_v2 ↗gnomad_v4 ↗

PM5 supporting Pathogenic

Met at supporting: the observed p.Gln350HisfsTer11 frameshift terminates at codon 360, upstream of the PALB2 VCEP PM5 cutoff p.His1184.

PALB2 VCEP v1.3 PM5_supporting applies to NMD-prone DNA truncating variants receiving PVS1 at Very Strong strength with premature termination codons upstream of p.His1184.The case variant is a frameshift, p.(Gln350HisfsTer11), placing the premature termination at codon 360, upstream of p.His1184.PMID:18446436 directly reports the same truncating frameshift as 1050_1051delAAinsTCT in a breast-cancer family.

cspec ↗PMID:18446436 ↗

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

Pathogenic

PS4 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.

PP1 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.

Benign

BA1 Not met: the variant is absent from gnomAD v2.1 and v4.1, so no allele frequency exceeds PALB2's >0.1% BA1 threshold.

BS1 Not met: the variant is absent from gnomAD v2.1 and v4.1, so no allele frequency exceeds PALB2's >0.01% BS1 threshold.

BS2 Not assessed: no documented homozygote or unaffected-carrier observations are available to meet PALB2's BS2 point thresholds.

BS4 Not assessed: no non-segregation was reported, and no quantitative LOD or LR was provided to compare with the BS4 thresholds.

N/A · 19 PS1 · PS2 · PS3 · PM1 · PM3 · 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

Absent from gnomAD v4.1.

v2.1

Absent from gnomAD v2.1.

🇨🇦 CA

Not available in gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

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 but submission details could not be extracted. (ClinVarID = 126585)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).

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 ↗

Literature · how each cited paper was used

1papers cited

Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 7 further PMIDs triaged but not cited — see Sources & references.

The prevalence of PALB2 germline mutations in BRCA1/BRCA2 negative Chinese women with early onset breast cancer or affected relatives.

PMID 18446436 ↗ · Cao AY et al. · 2009 Apr CLINVAR · splicing rna

Searched

c.1050_1051delinsTCT1050_1051delAAinsTCTNP_078951.2:p.(Q350Hfs*11)

Found

This paper explicitly reports the same PALB2 variant as 1050_1051delAAinsTCT, a heterozygous truncating frameshift in exon 4 that produces a Q350 frameshift/fusion protein retaining only 349 residues of native PALB2. It was identified in one of 360 BRCA1/BRCA2-negative Chinese women with early-onset or familial breast cancer and was absent in 864 unaffected controls.

Variant

✓ Names this variant — characterised directly

Applied to

→PVS1 very strong

Direct report of the exact truncating frameshift variant in exon 4 and its resulting shortened PALB2 protein.

→PM5 supporting

Documents the same variant as an observed truncating frameshift, relevant to the PALB2 VCEP truncation-based PM5 rule.

A frameshift mutation, 1050_1051delAAinsTCT, was detected in a family with breast cancer history, the genetic testing about the proband’s mother indicated that this mutation was inherited from the maternal side.

Location Results, Clinical features of mutation carriers; Discussion; Tables 1–3; Fig. 2 · Context PALB2 mutation screening by PCR-DHPLC followed by bidirectional Sanger sequencing in 360 BRCA1/BRCA2-negative Chinese women with early-onset or familial breast cancer; comparison with 864 unaffected controls and family-member testing. · full text

Sources & reference links

9Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 7 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

19264984 ↗ Exomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene. CLINVAR

15604628 ↗ Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors. CLINVAR

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