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NM_024675.4:c.1049_1051delinsTTCT
p.Gln350LeufsTer11 · PALB2
ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PALB2 Version 1.3 · v1.3
0%
complete
Final classification
Pathogenic
PVS1PM2PM5
PALB2
c.1049_1051delinsTTCT
p.Gln350LeufsTer11
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

This early PALB2 truncating variant is expected to impair the tumor-suppressor protein's role in BRCA1/BRCA2-associated homologous-recombination DNA repair.

Transcript
NM_024675.4
HGVS · transcript:coding
NM_024675.4:c.1049_1051delinsTTCT
GRCh38
chr16:23635495 TTT>AGAA
GRCh37
chr16:23646816 TTT>AGAA
Pathogenic: PVS1 (very strong) plus PM2 and PM5 (supporting) satisfy Rule4 of the PALB2 VCEP Version 1.3 framework.
Classification rationale
PVS1PM2PM5 Pathogenic
PALB2 c.1049_1051delinsTTCT frameshift · exon 4

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.

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 · 7 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, very strong: frameshift p.(Q350Lfs*11) creates a premature stop 11 codons after Gln350 in coding exon 4, well upstream of p.His1184.
PALB2 VCEP Version 1.3 identifies frameshift variants as PVS1-eligible null variants and directs use of the PALB2 PVS1 decision tree.The normalized consequence is NM_024675.4:c.1049_1051delinsTTCT, NP_078951.2:p.(Q350Lfs*11), with the variant located in coding exon 4.The PALB2 VCEP states that the default disease-relevant transcript is NM_024675.3/ENST00000261584.8 and that described alternate isoforms are not candidate rescue transcripts.
cspec ↗pvs1_generic_framework ↗
PM2 supporting Pathogenic
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%.
The PALB2 VCEP Version 1.3 specifies PM2 Supporting at frequency <=1/300,000 (0.000333%) in the gnomAD subpopulation with the highest frequency.The variant is absent from gnomAD v2.1 and gnomAD v4.1; the observed allele frequency is therefore 0, below the VCEP threshold.The available gnomAD non-cancer searches also report absence; the VCEP does not require a non-cancer-only or exome-only source for this rule, so the all-comers gnomAD entries are the governing default.
cspec ↗gnomad_v2 ↗gnomad_v4 ↗
PM5 supporting Pathogenic
Met, supporting: PALB2 PM5 applies to NMD-prone PVS1-very-strong truncations upstream of His1184, and this Q350 frameshift terminates near residue 360.
The PALB2 VCEP PM5 rule assigns supporting evidence to NMD-prone truncating variants receiving PVS1 at Very Strong with premature termination codons upstream of p.His1184.The variant is NM_024675.4:c.1049_1051delinsTTCT, annotated as NP_078951.2:p.(Q350Lfs*11), so the premature termination occurs around residue 360, upstream of His1184.The PALB2 VCEP PVS1 materials establish the loss-of-function framework for PALB2, and the case PVS1 assessment identifies this as a frameshift evaluated under that framework with a suggested default strength of very strong.
cspec ↗
Assessed · not applied · 2 not met · 5 not assessed
Pathogenic
PS4 Not assessed: aggregate PALB2 truncating variants had OR 4.69, but the study did not report this exact variant.
PM3 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.
PP1 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.
Benign
BA1 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.
BS1 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.
BS2 Not assessed: the PALB2 VCEP excludes population cohorts such as gnomAD for BS2, and no qualifying healthy-adult or homozygote observation is available.
BS4 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.
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 screenshot
gnomAD v4.1
gnomAD v2.1 screenshot
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 screenshot
ClinVar
This variant is absent from ClinVar.
ClinVar ↗
SpliceAI screenshot
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
SpliceAI ↗
Functional / OncoKB screenshot
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 screenshot
COSMIC
Cancer hotspots screenshot
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 · 5 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