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NM_024675.4:c.2052del
p.Arg686GlyfsTer23 · PALB2
ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PALB2 Version 1.2 · v1.2
0%
complete
Final classification
Likely Pathogenic
PVS1PM5
PALB2
c.2052del
p.Arg686GlyfsTer23
frameshift · exon 5
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 truncating variant is relevant to hereditary cancer susceptibility because PALB2 supports BRCA2- and BRCA1-associated homologous-recombination DNA repair, and inherited loss of function increases breast, ovarian, pancreatic, and prostate cancer risk.

Transcript
NM_024675.4
HGVS · transcript:coding
NM_024675.4:c.2052del
GRCh38
chr16:23630101 TG>T
GRCh37
chr16:23641422 TG>T
Likely Pathogenic: PALB2 VCEP Rule19 is satisfied by PVS1 (very strong) plus PM5 (supporting).
Classification rationale
PVS1PM5 Likely Pathogenic
PALB2 c.2052del frameshift · exon 5

PVS1 very strong: c.2052del creates a premature truncation in PALB2, where loss of function is an established disease mechanism. PM5 supporting: p.Arg686GlyfsTer23 terminates upstream of the PALB2 VCEP p.Tyr1183 cutoff.

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: c.2052del creates p.Arg686GlyfsTer23, a premature truncation in PALB2, an established loss-of-function disease gene.
The PALB2 Version 1.2 specification identifies PVS1 as applicable through the PALB2 PVS1 decision tree and identifies PM4 and BP3 as not applicable.The variant is NM_024675.4:c.2052del, a frameshift predicted as NP_078951.2:p.(Arg686GlyfsTer23).PALB2 loss of function is an established disease mechanism in the governing gene-specific framework.
cspec ↗pvs1_generic_framework ↗PMID:25741868 ↗
PM5 supporting Pathogenic
Met, Supporting: p.Arg686GlyfsTer23 terminates near residue 708, upstream of the PALB2 VCEP cutoff p.Tyr1183.
The governing PALB2 Version 1.2 PM5 rule applies Supporting evidence to frameshifting or truncating variants with premature termination codons upstream of p.Tyr1183.Variant normalization predicts p.(Arg686GlyfsTer23), with the premature termination at approximately residue 708, which is upstream of p.Tyr1183.
cspec ↗
Assessed · not applied · 4 not met · 4 not assessed
Pathogenic
PS4 Not assessed: the exact-variant case-control odds ratio, p-value, and lower 95% confidence bound required by the PALB2 PS4 rule are not available.
PM2 Not met: gnomAD v4.1 total AF is 0.00154888%, above the PALB2 PM2 cutoff of <=0.000333%.
PM3 Not assessed: no affected-proband observation or documented phase with a pathogenic PALB2 variant in trans is available for c.2052del.
PP1 Not assessed: no exact-variant pedigree, affected-relative count, LOD score, or Bayes factor is available to compare with the VCEP PP1 thresholds.
Benign
BA1 Not met: gnomAD v4.1 grpmax FAF is 0.001454%, below the PALB2 BA1 threshold of >0.1%.
BS1 Not met: gnomAD v4.1 grpmax FAF is 0.001454%, below the PALB2 BS1 threshold of >0.01%.
BS2 Not met: gnomAD v4.1 reports zero homozygotes, providing no PALB2 BS2 points toward the 1-point supporting threshold.
BS4 Not assessed: no exact-variant non-segregation data or quantitative LOD/LR result is available to compare with the VCEP BS4 thresholds.
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
This variant is present in gnomAD v4.1 (AF= 1.54888e-05; MAF= 0.00155%, 25/1614070 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 2.11856e-05; MAF= 0.00212%, 25/1180048 alleles, homozygotes = 0); grpmax FAF= 1.454e-05.
v2.1
This variant is present in gnomAD v2.1 (AF= 7.95355e-06; MAF= 0.00080%, 2/251460 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.75812e-05; MAF= 0.00176%, 2/113758 alleles, homozygotes = 0); grpmax FAF= 2.92e-06.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.0015% · 25 / 1,614,070
0 hom · FAF 0.0015%
European (non-Finnish)
25 / 1,180,048
0.0021%
+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.0008% · 2 / 251,460
0 hom · FAF 0.00029%
European (non-Finnish)
2 / 113,758
0.0018%
+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)
gnomAD Canada 🇨🇦
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗
ClinVar screenshot
ClinVar
This variant has been reported in ClinVar as Pathogenic (13 clinical laboratories). (ClinVarID = 142733)
ClinVar ↗
SpliceAI screenshot
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).
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 ↗
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.
Rule & framework references · cited for criterion definitions, not variant evidence
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.
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
17200671 ↗ Biallelic mutations in PALB2 cause Fanconi anemia subtype FA-N and predispose to childhood cancer. CLINVAR
25099575 ↗ Breast-cancer risk in families with mutations in PALB2. CLINVAR