NM_018062.3:c.238C>G (p.Leu80Val) in FANCL is a missense variant observed at very low frequency in gnomAD (overall AF 0.015–0.018%) but with two homozygotes in gnomAD v4.1, which is unexpected for a fully penetrant autosomal recessive Fanconi anemia gene.1 Multiple computational tools predict a benign effect: REVEL score 0.193, BayesDel score -0.271, and SpliceAI max delta 0.04, providing supporting evidence against pathogenicity (BP4_Supporting).2 No functional studies, segregation data, de novo reports, or case-control data are available for this variant. It has been reported in ClinVar as Uncertain significance by six clinical laboratories with no expert panel review.3 No variant-specific evidence was identified in the literature. All ClinVar-associated publications are general guidelines (ACMG/AMP, Sherloc), carrier screening recommendations, GeneReviews, or PDQ cancer genetics summaries that do not mention or evaluate this specific variant.4 Under generic ACMG/AMP 2015 criteria, the available evidence yields one supporting pathogenic criterion (PM2_Supporting) and one supporting benign criterion (BP4_Supporting), resulting in an Uncertain significance classification.5
FANCL
Final classification
VUS
FANCL c.238C>G · p.Leu80Val
FANCL
NM_018062.3:c.238C>G (p.Leu80Val) in FANCL is a missense variant observed at very low frequency in gnomAD (overall AF 0.015–0.018%) but with two homozygotes in gnomAD v4.1, which is unexpected for a fully penetrant autosomal recessive Fanconi anemia gene.
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 benign; combination = 1 supporting + 1 supporting benign, which maps to VUS.
Classification rationale
PM2
BP4
VUS
FANCL c.238C>G
PM2 + BP4
→
VUS
2
revelbayesdelspliceai ↗
5
generic_acmg_combination_rules
Gene diagram
· NM_018062.3 · variants mapped to exon structure
FANCL
NM_018062.3
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 21 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
review
Pathogenic
This variant is present at very low frequency in gnomAD (v2.1 overall AF=0.018%; v4.1 overall AF=0.015%), meeting the PM2 supporting threshold of <0.1% for non-VCEP assessment. However, caution is warranted: gnomAD v4.1 reports two homozygotes (including one in the Middle Eastern population), which is unexpected for an autosomal recessive severe pediatric disorder and raises the possibility that this variant may not be fully penetrant.
gnomAD v2.1: 51/282272 alleles (AF=0.018%)0 homozygotes
✓
BP4
supporting
Benign
Multiple lines of computational evidence suggest no impact on the gene product: REVEL score is 0.193 (benign range), BayesDel score is -0.271 (predicts benign), and SpliceAI predicts no splicing impact (max delta 0.04).
REVEL: 0.193 (below 0.5 pathogenic thresholdin benign range).BayesDel: -0.271 (negative
Assessed · not applied
Pathogenic
PS1
No alternative nucleotide change at c.238 resulting in the same amino acid change (p.Leu80Val) was identified in ClinVar or the literature.
PS2
No de novo reports with confirmed maternity and paternity were identified for this variant in ClinVar or the literature.
PS3
No well-established in vitro or in vivo functional studies have been performed specifically for NM_018062.3:c.238C>G (p.Leu80Val).
PS4
No case-control study data or statistically significant enrichment in affected individuals is available for this variant.
PM1
Residue Leu80 does not lie in a statistically significant mutational hotspot in FANCL (Hotspots: residue_significant=false).
PM5
No same-residue comparator missense variants were identified at codon 80 of FANCL in ClinVar.
PM6
No de novo observations (with or without confirmed parentage) were identified for this variant in ClinVar or the literature.
PP1
No cosegregation data in affected family members is available for this variant.
PP2
PP2 requires a gene with a low rate of benign missense variation where missense is a common disease mechanism.
PP3
Multiple in silico predictors do not support a deleterious effect: REVEL score is 0.193 (below the 0.5 pathogenic threshold), BayesDel score is -0.271 (predicts benign), and SpliceAI delta score is 0.04 (no predicted splicing impact).
PP4
No patient phenotype or family history data are available to assess whether the clinical presentation is highly specific for Fanconi anemia with a single genetic etiology.
PP5
No reputable source has classified this variant as pathogenic.
Benign
BA1
Allele frequency in all gnomAD populations is well below 1%.
BS1
Allele frequency does not exceed 0.3% in any gnomAD population.
BS2
While gnomAD v4.1 reports 2 homozygotes for this variant, the clinical status of these individuals is unknown.
BS3
No well-established functional studies demonstrating no damaging effect have been performed for this specific variant.
BS4
No segregation data are available to assess lack of cosegregation with disease in affected family members.
BP1
BP1 requires a gene where only truncating variants cause disease.
BP2
No phasing data are available to determine whether this variant has been observed in trans with a pathogenic FANCL variant or in cis with a pathogenic variant in any individual.
BP5
No data are available indicating this variant was found in a case with an alternative molecular basis for disease.
BP6
No reputable source has classified this variant as benign.
N/A · 3
PVS1 · BP3 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 0.000149416; MAF= 0.01494%, 241/1612942 alleles, homozygotes = 2) and has highest observed frequency in the Middle Eastern population (AF= 0.00165399; MAF= 0.16540%, 10/6046 alleles, homozygotes = 1); grpmax FAF= 0.00089698.
v2.1
This variant is present in gnomAD v2.1 (AF= 0.000180677; MAF= 0.01807%, 51/282272 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.000818491; MAF= 0.08185%, 25/30544 alleles, homozygotes = 0); grpmax FAF= 0.00056865.
🇨🇦 CA
Not available in gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.015%
· 241 / 1,612,942
2 hom · FAF 0.09%
2 hom · FAF 0.09%
Middle Eastern 10 / 6,046 |
0.17% 1 hom |
South Asian 71 / 90,974 |
0.078% 1 hom |
Remaining individuals 11 / 62,466 |
0.018% |
Admixed American 9 / 59,944 |
0.015% |
European (non-Finnish) 140 / 1,179,544 |
0.012% |
+ 5 not observed (European (Finnish), Amish, East Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.018%
· 51 / 282,272
0 hom · FAF 0.057%
0 hom · FAF 0.057%
South Asian 25 / 30,544 |
0.082% |
Remaining individuals 2 / 7,200 |
0.028% |
European (non-Finnish) 20 / 128,888 |
0.016% |
Admixed American 4 / 35,376 |
0.011% |
+ 4 not observed (African/African American, Ashkenazi Jewish, East Asian, European (Finnish))
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 (6 clinical laboratories). (ClinVarID = 408230)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04). REVEL score = 0.193. BayesDel score = -0.271414.
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 not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
Triaged references · 6 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
26389258 ↗
Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Version.
CLINVAR