NM_024675.4:c.886dupA (p.Met296AsnfsTer7) is a frameshift duplication in exon 4 of PALB2 that introduces a premature termination codon predicted to trigger nonsense-mediated decay, meeting PVS1 at very strong strength under the ClinGen PALB2 VCEP v1.2.0.1 The variant is present in gnomAD v4.1 at an overall frequency of 0.00031% (5/1,613,880 alleles, no homozygotes), below the PALB2 VCEP PM2_Supporting threshold of 0.000333%, satisfying PM2 at supporting strength.2 The premature termination codon at residue 302 lies upstream of p.Tyr1183, the most C-terminal known pathogenic variant in PALB2, satisfying PM5_Supporting under the PALB2 VCEP.3 Under the ACMG/AMP 2015 combining rules adopted by the PALB2 VCEP, one Very Strong (PVS1) plus two Supporting (PM2, PM5) criteria satisfies Rule 4, yielding a classification of Pathogenic.4
PALB2
Final classification
Pathogenic
PALB2 c.886dup · p.Met296AsnfsTer7
PALB2
NM_024675.4:c.886dupA (p.Met296AsnfsTer7) is a frameshift duplication in exon 4 of PALB2 that introduces a premature termination codon predicted to trigger nonsense-mediated decay, meeting PVS1 at very strong strength under the ClinGen PALB2 VCEP v1.2.0.
Richards et.al., 2015 - Combining rules v1.2.0 criteria-combination framework: matched Rule4 (1 Pathogenic.Very Strong + Pathogenic.Supporting >=2) with applied criteria: PVS1 very strong, PM2 supporting, PM5 supporting; maps to Pathogenic.
Classification rationale
PVS1PM2PM5
Pathogenic
PALB2 c.886dup
PVS1 + PM2 + PM5
→
Pathogenic
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
Applied · 3
Strength
Supporting
Moderate
Strong
Very strong
✓
PVS1
very strong
Pathogenic
This frameshift duplication in exon 4 introduces a premature termination codon at position 302 (p.Met296AsnfsTer7), far upstream of the most C-terminal known PALB2 pathogenic variant (p.Tyr1183), and is predicted to trigger nonsense-mediated decay. PALB2 loss of function is an established disease mechanism under the ClinGen PALB2 VCEP (v1.2.0).
Frameshift variant predicted to cause NMD (stop at codon 302 in exon 4 of 13)Truncation upstream of p.Tyr1183the most C-terminal known pathogenic variant in PALB2
✓
PM2
supporting
Pathogenic
This variant has an overall allele frequency of 0.00031% (5/1,613,880 alleles) in gnomAD v4.1, which is below the PALB2 VCEP PM2_Supporting threshold of ≤0.000333% (1/300,000). No homozygotes have been observed.
gnomAD v4.1 overall frequency: 0.00031% (5/1613880)
✓
PM5
supporting
Pathogenic
This frameshift variant introduces a premature termination codon at position 302 (p.Met296AsnfsTer7), upstream of the most C-terminal known PALB2 pathogenic variant (p.Tyr1183), satisfying the PALB2 VCEP PM5_Supporting rule for truncating variants.
Premature termination codon at residue 302upstream of p.Tyr1183 cutoffConsistent with PALB2 VCEP PM5_Supporting rule for frameshifting variants
Assessed · not applied
Pathogenic
PS4
No case-control study has been identified that evaluates NM_024675.4:c.886dupA specifically with an odds ratio ≥3 or lower 95% CI ≥1.5 and p≤0.05, as required by the PALB2 VCEP PS4 rule.
PP1
No co-segregation data (LOD scores, Bayes factors, or affected relative counts) are available for NM_024675.4:c.886dupA.
Benign
BA1
The grpmax filtering allele frequency for this variant is 0.00175% (grpmax FAF = 1.747e-05) in gnomAD v4.1, well below the BA1 threshold of >0.1%.
BS1
The grpmax filtering allele frequency for this variant is 0.00175% (grpmax FAF = 1.747e-05) in gnomAD v4.1, below the BS1 threshold of >0.01%.
BS2
No individuals homozygous or compound heterozygous for this variant have been reported with a Fanconi anemia phenotype, and no BS2 proband-level data are available for point assignment under the PALB2 VCEP Fanconi Anemia BS2 tables.
BS4
No segregation data demonstrating lack of co-segregation (LOD ≤ -0.32 or Bayes Factor ≤0.48) with disease is available for this variant.
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= 3.09812e-06; MAF= 0.00031%, 5/1613880 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 5.34259e-05; MAF= 0.00534%, 4/74870 alleles, homozygotes = 0); grpmax FAF= 1.747e-05.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00031%
· 5 / 1,613,880
0 hom · FAF 0.0017%
0 hom · FAF 0.0017%
African/African American 4 / 74,870 |
0.0053% |
East Asian 1 / 44,882 |
0.0022% |
+ 8 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, Middle Eastern, South Asian, Ashkenazi Jewish, European (non-Finnish))
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Pathogenic (8 clinical laboratories). (ClinVarID = 410157)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
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.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV55163417, n = 3 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
9Sources
Triaged references · 9 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
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
17200671 ↗
Biallelic mutations in PALB2 cause Fanconi anemia subtype FA-N and predispose to childhood cancer.
CLINVAR
25741868 ↗
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR