NM_024675.4:c.1209G>A (p.Leu403=) is a synonymous variant in exon 4 of PALB2 with no predicted splicing impact (SpliceAI max delta 0.00), meeting BP7_Supporting per PALB2 VCEP v1.2.0.1 SpliceAI predicts no splicing impact (max delta 0.00, below VCEP threshold of 0.1), meeting BP4_Supporting per PALB2 VCEP v1.2.0.2 The variant is present in gnomAD v4.1 at a total allele frequency of 4.34×10⁻⁶ (7/1,614,016 alleles, grpmax FAF 7.9×10⁻⁷), exceeding the VCEP PM2_Supporting threshold of 3.33×10⁻⁶; PM2 is not met.3 ClinVar reports this variant as Likely benign (6 clinical laboratories) and Benign (1 clinical laboratory); no expert panel has classified it as pathogenic (VariationID: 185784).4 No published literature was identified that directly references NM_024675.4:c.1209G>A. Eight papers retrieved from ClinVar and OncoKB sources were reviewed; none mention the specific variant.5
PALB2
Final classification
Likely Benign
PALB2 c.1209G>A · p.Leu403=
PALB2
NM_024675.4:c.1209G>A (p.Leu403=) is a synonymous variant in exon 4 of PALB2 with no predicted splicing impact (SpliceAI max delta 0.00), meeting BP7_Supporting per PALB2 VCEP v1.2.0.
Richards et.al., 2015 - Combining rules v1.2.0 criteria-combination framework: matched Rule19 (Benign.Supporting >=2) with applied criteria: BP4 supporting benign, BP7 supporting benign; maps to Likely Benign.
Classification rationale
BP4BP7
Likely Benign
PALB2 c.1209G>A
BP4 + BP7
→
Likely Benign
Gene diagram
· NM_024675.4 · variants mapped to exon structure
PALB2
NM_024675.4
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 9 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
BP4
supporting
Benign
SpliceAI predicts no splicing impact for this synonymous variant (max delta score = 0.00, ≤0.1 VCEP threshold). Per PALB2 VCEP v1.2.0, BP4_Supporting may be applied for splicing assessment when SpliceAI ≤0.1.
SpliceAI max delta = 0.00 — no predicted splice impactVCEP BP4 splicing threshold: SpliceAI ≤ 0.1 (met)
✓
BP7
supporting
Benign
NM_024675.4:c.1209G>A is a synonymous variant (p.Leu403=) located in exon 4 at position c.1209, far from splice donor (475 nt from +1) and acceptor (997 nt from -1) sites. SpliceAI predicts no splicing impact (max delta = 0.00). Per PALB2 VCEP v1.2.0, BP7_Supporting applies to synonymous variants beyond ±7/21 of splice consensus sites.
Synonymous substitution p.(Leu403=)Located deep in exon 4far from splice boundaries (475 nt from donor
Assessed · not applied
Pathogenic
PS4
No case-control study data are available for NM_024675.4:c.1209G>A.
PM2
The gnomAD v4.1 total allele frequency is 4.34×10⁻⁶ (7/1,614,016 alleles), which exceeds the PALB2 VCEP PM2_Supporting threshold of ≤3.33×10⁻⁶ (≤0.000333%, 1/300,000).
PP1
No co-segregation data are available for NM_024675.4:c.1209G>A.
PP3
Per VCEP, PP3 is not used for missense variants and requires SpliceAI ≥0.2 for splicing assessment.
Benign
BA1
The gnomAD v4.1 grpmax filtering allele frequency is 7.9×10⁻⁷ (0.000079%), far below the PALB2 VCEP BA1 threshold of >0.1%.
BS1
The gnomAD v4.1 grpmax filtering allele frequency is 7.9×10⁻⁷ (0.000079%), below the PALB2 VCEP BS1 threshold of >0.01%.
BS2
No proband-level data are available for BS2 assessment.
BS4
No co-segregation data are available to calculate a LOD score or Bayes Factor for lack of segregation.
BP1
Per VCEP, BP1 applies to all missense variants in PALB2 (low rate of functional missense variants).
N/A · 14
PVS1 · PS1 · PS2 · PS3 · PM1 · PM5 · PM6 · PP2 · PP4 · PP5 · BS3 · BP2 · BP5 · BP6
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 4.33701e-06; MAF= 0.00043%, 7/1614016 alleles, homozygotes = 0) and has highest observed frequency in the Middle Eastern population (AF= 0.000165017; MAF= 0.01650%, 1/6060 alleles, homozygotes = 0); grpmax FAF= 7.9e-07.
v2.1
This variant is present in gnomAD v2.1 (AF= 3.986e-06; MAF= 0.00040%, 1/250878 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.82426e-06; MAF= 0.00088%, 1/113324 alleles, homozygotes = 0).
🇨🇦 CA
Not available in gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00043%
· 7 / 1,614,016
0 hom · FAF 7.9e-05%
0 hom · FAF 7.9e-05%
Middle Eastern 1 / 6,060 |
0.017% |
Remaining individuals 2 / 62,508 |
0.0032% |
European (non-Finnish) 4 / 1,180,030 |
0.00034% |
+ 7 not observed (Admixed American, European (Finnish), Amish, East Asian, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.0004%
· 1 / 250,878
0 hom
0 hom
European (non-Finnish) 1 / 113,324 |
0.00088% |
+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Likely benign (6 clinical laboratories) and as Benign (1 clinical laboratory). (ClinVarID = 185784)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
Functional
Unknown Oncogenic Effect
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
COSMIC
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.
Sources & reference links
9Sources
Triaged references · 8 PMIDs not cited in assessment
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
26467025 ↗
A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.
CLINVAR
15604628 ↗
Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors.
CLINVAR
26389258 ↗
Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Version.
CLINVAR
31429903 ↗
Risk Assessment, Genetic Counseling, and Genetic Testing for BRCA-Related Cancer: US Preventive Services Task Force Recommendation Statement.
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR