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NM_024675.4:c.1049_1050insT
p.Gln350HisfsTer11 · 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_1050insT
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

This PALB2 frameshift is relevant to disease because PALB2 loss disrupts BRCA1/BRCA2-associated homologous-recombination repair, increasing inherited cancer susceptibility and, when biallelic, causing Fanconi anemia complementation group N.

Transcript
NM_024675.4
HGVS · transcript:coding
NM_024675.4:c.1049_1050insT
GRCh38
chr16:23635496 T>TA
GRCh37
chr16:23646817 T>TA
Pathogenic: PVS1 very strong plus PM2 and PM5 supporting satisfy Rule4 of the PALB2 Version 1.3 VCEP framework.
Classification rationale
PVS1PM2PM5 Pathogenic
PALB2 c.1049_1050insT frameshift · exon 4

Pathogenic: PVS1 very strong applies to the early PALB2 frameshift truncation near residue 360. Pathogenic: PM2 supporting applies because the variant is absent from evaluated gnomAD datasets. Pathogenic: PM5 supporting applies because the premature stop is upstream of p.His1184 under the PALB2 VCEP truncation rule.

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: the early frameshift p.(Q350Hfs*11) truncates PALB2 near residue 360, far upstream of the VCEP p.His1184 cutoff.
The PALB2 VCEP Version 1.3 identifies nonsense and frameshift variants as PVS1-eligible null variants when PALB2 loss of function is a known disease mechanism, with caution for extreme 3-prime truncations and splice events that leave the remainder of the protein intact.The VCEP materials specify NM_024675.3/ENST00000261584.8 as the default RefSeq transcript; NM_024675.4 is the compatible version used for this case and yields p.(Q350Hfs*11).The variant assessment gives a frameshift consequence and p.(Q350Hfs*11), placing the predicted premature termination around residue 360, well upstream of the PALB2 VCEP p.His1184 cutoff.
cspec ↗pvs1_generic_framework ↗
PM2 supporting Pathogenic
Met at supporting strength: the variant is absent from gnomAD v2.1, v4.1, and non-cancer subsets, giving observed frequency 0 versus the PALB2 threshold of 0.000333%.
PALB2 VCEP Version 1.3 specifies PM2 supporting for frequency <=1/300,000 (0.000333%) in the gnomAD subpopulation with the highest frequency; it also permits a single observation confined to one subpopulation.The variant is absent from gnomAD v2.1 and gnomAD v4.1, corresponding to observed frequency 0 in those datasets.The variant is absent from the available gnomAD v2.1 non-cancer and gnomAD v3.1 non-cancer subsets as well.
cspec ↗gnomad_v2 ↗gnomad_v4 ↗
PM5 supporting Pathogenic
Met, supporting: p.Gln350HisfsTer11 creates a premature stop near His360, upstream of the PALB2 VCEP cutoff p.His1184 and within its PVS1-Very Strong truncation rule.
The PALB2 VCEP PM5 rule applies at supporting strength to NMD-prone truncating variants receiving PVS1 at Very Strong strength with premature termination codons upstream of p.His1184.The variant-level consequence is a frameshift, NP_078951.2:p.(Gln350HisfsTer11), placing the premature termination codon near His360, upstream of His1184.The PALB2 VCEP PVS1 materials establish loss of function as a relevant disease mechanism, and the variant-level PVS1 assessment identifies this frameshift as eligible for the generic PVS1 framework with suggested Very Strong strength.
cspec ↗
Assessed · not applied · 2 not met · 5 not assessed
Pathogenic
PS4 Not assessed: group-level PALB2 truncating-variant enrichment was OR 4.69, but no exact-variant case-control statistic is available for c.1049_1050insT.
PM3 Not assessed: no affected-proband observation or confirmed phase with a pathogenic PALB2 variant is documented for c.1049_1050insT.
PP1 Not assessed: no affected-relative segregation data, meioses, LOD score, or likelihood ratio are available to compare with 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, so its frequency is not greater than the PALB2 VCEP BA1 threshold of 0.1%.
BS1 Not met: the variant is absent from gnomAD v2.1 and v4.1, so its frequency does not exceed the PALB2 VCEP BS1 threshold of 0.01%.
BS2 Not assessed: no homozygote, unaffected-carrier, phenotype, or PALB2 VCEP BS2 point data are available for this absent variant.
BS4 Not assessed: no affected non-carriers, non-segregation observations, LOD score, or likelihood ratio are available to compare with the BS4 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