PVS1 at moderate strength: c.2T>C is a start-loss variant abolishing the FANCL initiation codon with no alternative in-frame ATG in exon 1. Loss of function is an established disease mechanism for Fanconi anemia.1 PM2 at supporting strength: This variant is present at very low frequency in gnomAD (v2.1 AF=0.00478%; v4.1 AF=0.00347%), with no homozygotes observed, consistent with a rare pathogenic variant.2 Overall classification: Uncertain Significance (VUS). The combination of PVS1_Moderate and PM2_Supporting does not meet the threshold for Likely Pathogenic per ACMG/AMP 2015 combination rules (requires ≥2 Moderate or ≥1 Moderate + ≥4 Supporting). ClinVar submissions report Pathogenic/Likely Pathogenic but are limited to single-submitter review and cite evidence not independently verifiable in available full-text literature.3
FANCL
Final classification
VUS
FANCL c.2T>C · p.Met1?
FANCL
PVS1 at moderate strength: c.2T>C is a start-loss variant abolishing the FANCL initiation codon with no alternative in-frame ATG in exon 1. Loss of function is an established disease mechanism for Fanconi anemia.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PVS1 moderate, PM2 supporting; combination = 1 moderate + 1 supporting, which maps to VUS.
Classification rationale
PVS1PM2
VUS
FANCL c.2T>C
PVS1 + PM2
→
VUS
1
pvs1_generic_framework ↗pvs1_gene_context
3
generic_acmg_combination_rulesclinvar ↗
Gene diagram
· NM_018062.3 · variants mapped to exon structure
FANCL
NM_018062.3
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 18 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PVS1
moderate
Pathogenic
This start-loss variant (c.2T>C, p.Met1?) abolishes the initiation codon of FANCL. Loss of function is an established disease mechanism for FANCL (Fanconi anemia, autosomal recessive). Per ClinGen SVI PVS1 recommendations (PMC6185798), initiation codon variants qualify for PVS1 at moderate strength when no alternative in-frame start codon is present in the same exon. No downstream ATG was identified in FANCL exon 1.
Start-loss variant: c.2T>C changes initiation codon ATG to ACGFANCL loss of function causes Fanconi anemia (autosomal recessive)No alternative in-frame ATG in exon 1
✓
PM2
supporting
Pathogenic
This variant is present at very low frequency in population databases: gnomAD v2.1 AF=0.00478% (12/250,878 alleles, 0 homozygotes) and gnomAD v4.1 AF=0.00347% (56/1,614,008 alleles, 0 homozygotes). Both are well below the 0.1% threshold for PM2. The variant is absent from gnomAD-Canada.
gnomAD v2.1: AF=0.00478%12/250878 alleles
Assessed · not applied
Pathogenic
PS2
No de novo observation reported for this variant in any accessible data source.
PS3
No variant-specific functional studies were identified.
PS4
No case-control data or statistical enrichment analysis is available.
PM1
The variant is located at the initiation codon, a critical functional element.
PM6
No de novo observation reported.
PP1
No segregation data available for this variant.
PP3
In silico predictions are mixed and inconclusive.
PP4
ClinVar submissions report this variant in individuals with Fanconi anemia and various cancers.
PP5
ClinVar classifies this variant as Pathogenic (VariationID: 566870).
Benign
BA1
gnomAD allele frequency (0.00478% v2.1, 0.00347% v4.1) is well below the 1% BA1 threshold.
BS1
gnomAD allele frequency (0.00478% v2.1, 0.00347% v4.1) is well below the 0.3% BS1 threshold.
BS2
No evidence that this variant has been observed in a healthy adult individual in the homozygous state, or in trans with a pathogenic variant in a healthy individual.
BS3
No functional studies demonstrating no damaging effect for this variant.
BS4
No segregation data available to assess lack of segregation with disease.
BP2
No data on observation in trans with a pathogenic variant in FANCL, a recessive disorder.
BP4
In silico predictions are mixed.
BP5
No evidence of an alternate molecular basis for disease in a case carrying this variant.
BP6
ClinVar classifies this variant as Pathogenic, not benign.
N/A · 5
PS1 · PM5 · PP2 · BP1 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 3.46962e-05; MAF= 0.00347%, 56/1614008 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 4.49144e-05; MAF= 0.00449%, 53/1180022 alleles, homozygotes = 0); grpmax FAF= 3.503e-05.
v2.1
This variant is present in gnomAD v2.1 (AF= 4.7832e-05; MAF= 0.00478%, 12/250878 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000105764; MAF= 0.01058%, 12/113460 alleles, homozygotes = 0); grpmax FAF= 6.027e-05.
🇨🇦 CA
This variant is present in gnomAD-Canada v1.0 (AF= 0.0002171788467803236, 4/18418 alleles, homozygotes = 0).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.0035%
· 56 / 1,614,008
0 hom · FAF 0.0035%
0 hom · FAF 0.0035%
European (non-Finnish) 53 / 1,180,022 |
0.0045% |
Remaining individuals 2 / 62,484 |
0.0032% |
European (Finnish) 1 / 63,958 |
0.0016% |
+ 7 not observed (Admixed American, Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.0048%
· 12 / 250,878
0 hom · FAF 0.006%
0 hom · FAF 0.006%
European (non-Finnish) 12 / 113,460 |
0.011% |
+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)
gnomAD Canada 🇨🇦
0.022%
· 4 / 18,418
0 hom · FAF 0.012%
0 hom · FAF 0.012%
European (non-Finnish) 4 / 11,738 |
0.034% |
+ 8 not observed (African/African American, Latino/Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Middle Eastern, Remaining individuals, South Asian)
ClinVar
This variant has been reported in ClinVar as Pathogenic (3 clinical laboratories) and as Likely pathogenic (3 clinical laboratories) and as Uncertain significance (1 clinical laboratory). (ClinVarID = 566870)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.212. BayesDel score = 0.66.
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; COSV52073298, n = 2 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
Triaged references · 8 PMIDs not cited in assessment
20661450 ↗
Sex reversal in zebrafish fancl mutants is caused by Tp53-mediated germ cell apoptosis.
ONCOKB
25754594 ↗
Loss-of-Function FANCL Mutations Associate with Severe Fanconi Anemia Overlapping the VACTERL Association.
ONCOKB
30540754 ↗
Multiplexed CRISPR/Cas9-mediated knockout of 19 Fanconi anemia pathway genes in zebrafish revealed their roles in growth, sexual development and fertility.
ONCOKB
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
26149689 ↗
The Fanconi Anemia DNA Repair Pathway Is Regulated by an Interaction between Ubiquitin and the E2-like Fold Domain of FANCL.
CLINVAR
29335925 ↗
Germline deleterious mutations in genes other than BRCA2 are infrequent in male breast cancer.
CLINVAR