This variant is absent or extremely rare in large population cohorts: gnomAD v2.1 allele frequency 0.00389% (11/282,764 alleles) and v4.1 allele frequency 0.00229% (37/1,613,586 alleles), meeting PM2 at supporting level.1 Multiple in silico predictors do not support a deleterious effect: REVEL score 0.089, BayesDel score -0.494, and SpliceAI predicts no splicing impact (max delta 0.04), meeting BP4 at supporting level.2 The variant has been reported in ClinVar as Uncertain significance by 4 clinical laboratories and Likely benign by 1 clinical laboratory (ClinVar Variation ID: 898372). No expert panel classification is available.3 The variant is a missense substitution (p.Ala175Val) and does not qualify for PVS1. No functional studies, segregation data, case-control comparisons, or de novo observations were identified for this variant.4 Applying generic ACMG/AMP 2015 final combination rules (PMID:25741868): PM2_supporting and BP4_supporting provide conflicting lines of evidence with no other criteria met. The variant is classified as a Variant of Uncertain Significance (VUS).5
FANCL
Final classification
VUS
FANCL c.524C>T · p.Ala175Val
FANCL
This variant is absent or extremely rare in large population cohorts: gnomAD v2.1 allele frequency 0.00389% (11/282,764 alleles) and v4.1 allele frequency 0.00229% (37/1,613,586 alleles), meeting PM2 at supporting level.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, BP4 supporting; combination = 1 supporting + 1 supporting benign, which maps to VUS.
Classification rationale
PM2
BP4
VUS
FANCL c.524C>T
PM2 + BP4
→
VUS
Gene diagram
· NM_018062.3 · variants mapped to exon structure
FANCL
NM_018062.3
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 20 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
This variant is present at very low frequency in population databases: gnomAD v2.1 allele frequency 0.00389% (11/282,764 alleles) and v4.1 allele frequency 0.00229% (37/1,613,586 alleles), both well below the 0.1% PM2 threshold. No homozygotes observed.
gnomAD v2.1: AF=3.89e-5 (11/282764 alleles0 homozygotes)
✓
BP4
supporting
Benign
Multiple lines of computational evidence suggest no damaging effect: REVEL score 0.089 (benign), BayesDel score -0.494 (benign), and SpliceAI predicts no splicing impact (max delta 0.04).
REVEL: 0.089 (benignbelow 0.5 threshold)BayesDel: -0.494 (benign
Assessed · not applied
Pathogenic
PS1
No evidence of a different nucleotide change at codon 175 resulting in the same Ala175Val amino acid substitution that has been established as pathogenic.
PS2
No de novo data with confirmed maternity and paternity available for this variant.
PS3
No well-established functional studies demonstrating a damaging effect for NM_018062.3:c.524C>T were identified.
PS4
No case-control data or sufficient patient observations to assess whether the variant prevalence differs significantly between affected individuals and controls.
PM1
The variant is not located in a known mutational hotspot or well-established critical functional domain.
PM6
No de novo observations (with or without confirmed parentage) available for this variant.
PP1
No co-segregation data available for this variant.
PP2
Insufficient data to determine whether FANCL has a low rate of benign missense variation and a preponderance of pathogenic missense variants, which would be required for PP2 application.
PP3
Multiple in silico predictors do not support a deleterious effect: REVEL score 0.089 (well below the 0.5 threshold for pathogenicity), BayesDel score -0.494 (negative, favoring benign), and SpliceAI predicts no splicing impact (max delta 0.04).
PP4
No patient-specific phenotype or family history data available for review.
PP5
No reputable source has reported this variant as pathogenic.
Benign
BA1
The highest population allele frequency (gnomAD v2.1 European non-Finnish: 0.00697%) is far below the 1% threshold required for BA1.
BS1
The highest population allele frequency (0.00697%) is below the 0.3% threshold required for BS1.
BS2
No homozygous observations in gnomAD (v2.1: 0 homozygotes; v4.1: 0 homozygotes).
BS3
No well-established functional studies demonstrating no damaging effect for this specific variant were identified.
BS4
No segregation data available for this variant.
BP1
While FANCL is a gene in which biallelic loss-of-function variants cause Fanconi anemia, insufficient data are available to determine that primarily truncating (rather than missense) variants are the established cause of disease, which is required to apply BP1 to this missense variant.
BP2
FANCL is associated with disease through biallelic loss-of-function variants, not exclusively through missense changes.
BP5
No alternative missense variant at codon 175 with a benign classification was identified in ClinVar.
BP6
One ClinVar submitter (Ambry Genetics) classifies this variant as Likely benign, but four other clinical laboratories classify it as Uncertain significance.
N/A · 6
PVS1 · PM3 · PM4 · PM5 · BP3 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 2.29303e-05; MAF= 0.00229%, 37/1613586 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 0.000133329; MAF= 0.01333%, 8/60002 alleles, homozygotes = 0); grpmax FAF= 6.615e-05.
v2.1
This variant is present in gnomAD v2.1 (AF= 3.89017e-05; MAF= 0.00389%, 11/282764 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 6.96994e-05; MAF= 0.00697%, 9/129126 alleles, homozygotes = 0); grpmax FAF= 3.42e-05.
🇨🇦 CA
Not available in gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.0023%
· 37 / 1,613,586
0 hom · FAF 0.0066%
0 hom · FAF 0.0066%
Admixed American 8 / 60,002 |
0.013% |
European (non-Finnish) 27 / 1,179,588 |
0.0023% |
Remaining individuals 1 / 62,494 |
0.0016% |
African/African American 1 / 75,024 |
0.0013% |
+ 6 not observed (European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish)
gnomAD v2.1
0.0039%
· 11 / 282,764
0 hom · FAF 0.0034%
0 hom · FAF 0.0034%
European (non-Finnish) 9 / 129,126 |
0.007% |
Admixed American 2 / 35,424 |
0.0056% |
+ 6 not observed (African/African 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 Uncertain significance (4 clinical laboratories) and as Likely benign (1 clinical laboratory). (ClinVarID = 898372)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04). REVEL score = 0.089. BayesDel score = -0.494214.
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. FANCL, an E3 ubiquitin ligase involved in DNA repair, is infrequently altered in cancer. Germline mutations of FANCL are associated with the cancer pr
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; COSV99288152, n = 1 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
Triaged references · 6 PMIDs not cited in assessment
25626707 ↗
Whole-genome sequencing in newborn screening? A statement on the continued importance of targeted approaches in newborn screening programmes.
CLINVAR
25730230 ↗
Expanded carrier screening in reproductive medicine-points to consider: a joint statement of the American College of Medical Genetics and Genomics, American College of Obstetricians and Gynecologists, National Society of Genetic Counselors, Perinatal Quality Foundation, and Society for Maternal-Fetal Medicine.
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
23037933 ↗
Including the initial newborn screening bloodspot collection device serial number on birth certificates: basis and recommendations from the Secretary of Health and Human Services' Advisory Committee on Heritable Disorders in Newborns and Children.
CLINVAR