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NM_024675.4:c.2856T>G
p.Asp952Glu · 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
VUS
PM2BP1
PALB2
c.2856T>G
p.Asp952Glu
missense · exon 9
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 encodes a BRCA1- and BRCA2-interacting tumor suppressor that supports homologous-recombination DNA repair, and inherited PALB2 alterations increase susceptibility to breast cancer and several other cancers.

Transcript
NM_024675.4
HGVS · transcript:coding
NM_024675.4:c.2856T>G
GRCh38
chr16:23623109 A>C
GRCh37
chr16:23634430 A>C
VUS: PALB2 VCEP Rule31 combines PM2 supporting for rarity with BP1 supporting for the missense consequence, yielding conflicting supporting evidence.
Classification rationale
PM2 BP1 VUS
PALB2 c.2856T>G missense · exon 9

VUS: PM2 supporting reflects absence from gnomAD v2.1 and v4.1. VUS: BP1 supporting reflects the PALB2 VCEP rule for missense variants.

PM2 + BP1 → VUS
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 · 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 · 2
Strength Supporting Moderate Strong Very strong
PM2 supporting Pathogenic
Met at Supporting: gnomAD v2.1 and v4.1 report 0 observed alleles, below the PALB2 PM2 threshold of 0.000333%.
The PALB2 ClinGen VCEP Version 1.3 PM2 Supporting rule is frequency <=1/300,000 (0.000333%) in the gnomAD subpopulation with the highest frequency; the VCEP also permits a single-observation exception.The queried variant is absent from gnomAD v2.1 and gnomAD v4.1, with 0 observed alternate alleles and therefore an observed frequency of 0 in every assessed population.
cspec ↗gnomad_v2 ↗gnomad_v4 ↗
BP1 supporting Benign
Met at supporting strength: the PALB2 VCEP applies BP1 to all missense variants, and this variant is p.Asp952Glu.
The variant is annotated as NM_024675.4:c.2856T>G, NP_078951.2:p.(Asp952Glu), with missense consequence.The PALB2 Version 1.3 VCEP states that BP1 applies to all missense variants because true missense pathogenic variants are thought to be exceedingly rare, and specifies supporting strength.
cspec ↗
Assessed · not applied · 2 not met · 5 not assessed
Pathogenic
PS4 Not assessed: PALB2 VCEP PS4 requires p <= .05 and OR/HR/RR >=3 or lower 95% CI >=1.5, but no case-control estimate is available.
PM3 Not assessed: no affected Fanconi anemia proband, pathogenic second allele, or phase information is documented, so the VCEP PM3 point total is unavailable.
PP1 Not assessed: no family segregation data or quantitative result is available to compare with the PP1 supporting threshold of LOD ≥0.3 or LR ≥2:1.
Benign
BA1 Not met: gnomAD v2.1 and v4.1 report 0 observed alleles, below the PALB2 VCEP BA1 threshold of >0.1%.
BS1 Not met: gnomAD v2.1 and v4.1 report 0 observed alleles, below the PALB2 VCEP BS1 threshold of >0.01%.
BS2 Not assessed: gnomAD provides 0 observed alleles, but no qualifying healthy individual or homozygote observation is available for BS2.
BS4 Not assessed: no non-segregation observations or quantitative result is available to compare with the BS4 supporting threshold of LOD ≤−0.32 or LR ≤0.48.
N/A · 19 PVS1 · PS1 · PS2 · PS3 · PM1 · PM4 · PM5 · PM6 · PP2 · PP3 · PP4 · PP5 · BS3 · BP2 · BP3 · BP4 · BP5 · BP6 · BP7
Research & evidence
Population frequency
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
Absent from 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 has been reported in ClinVar as Uncertain significance (1 clinical laboratory). (ClinVarID = 963144)
ClinVar ↗
SpliceAI screenshot
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.14). REVEL score = 0.026. BayesDel score = -0.670448.
SpliceAI ↗
Functional / OncoKB screenshot
Functional Unknown Oncogenic Effect
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. PALB2, a scaffolding protein involved in DNA repair, is altered in various cancers.
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 · 6 PMIDs not cited in assessment
15604628 ↗ Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors. CLINVAR
17508274 ↗ Risk assessment and genetic counseling for hereditary breast and ovarian cancer: recommendations of the National Society of Genetic Counselors. CLINVAR
24366376 ↗ Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer in women: U.S. Preventive Services Task Force recommendation statement. CLINVAR
24432435 ↗ PMID 24432435 CLINVAR
28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification crite CLINVAR
34012068 ↗ ACMG SF v3.0 list for reporting of secondary findings in clinical exome and genome sequencing: a policy statement of the American College of Medical Genetics and Genomics (ACMG). CLINVAR