NM_018062.3:c.238C>G

FANCL · NP_060532.2:p.(Leu80Val) · NM_018062.3

GRCh37: chr2:58453898 G>C · GRCh38: chr2:58226763 G>C

Gene: FANCL Transcript: NM_018062.3

Final call

VUS

PM2 supporting BP4 supporting benign

Variant details

Gene

FANCL

Transcript

NM_018062.3

Protein

NP_060532.2:p.(Leu80Val)

gnomAD AF

0.00014941640802955096 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

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).

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.

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.

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.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	This is a missense variant (p.Leu80Val) and does not fall into the null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants required for generic PVS1 application per ClinGen SVI PVS1 recommendations (PMC6185798).	pvs1_generic_framework
PS1	Not assessed	No alternative nucleotide change at c.238 resulting in the same amino acid change (p.Leu80Val) was identified in ClinVar or the literature. No comparator variant available for PS1 assessment.
PS2	Not assessed	No de novo reports with confirmed maternity and paternity were identified for this variant in ClinVar or the literature.
PS3	Not met	No well-established in vitro or in vivo functional studies have been performed specifically for NM_018062.3:c.238C>G (p.Leu80Val). OncoKB reports Unknown Oncogenic Effect with no variant-specific functional evidence. No variant-specific functional data were identified in the literature.	oncokb
PS4	Not assessed	No case-control study data or statistically significant enrichment in affected individuals is available for this variant. The variant has been observed in clinical testing (6 ClinVar laboratories report Uncertain significance) but without case counts or phenotype-stratified prevalence data.	clinvar
PS5	Not assessed	PS5 requires a variant reported in affected individuals but without the statistical strength for PS4. No detailed case-level data describing affected individuals harboring this variant were available for independent evaluation.	clinvar
PM1	Not met	Residue Leu80 does not lie in a statistically significant mutational hotspot in FANCL (Hotspots: residue_significant=false). No evidence that codon 80 resides in a well-established critical functional domain devoid of benign missense variation.
PM2	Met	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 gnomad_v4
PM5	Not assessed	No same-residue comparator missense variants were identified at codon 80 of FANCL in ClinVar. Classic PM5 (different missense change at the same residue, with the comparator established as pathogenic) cannot be applied.	pm5_candidates
PM6	Not assessed	No de novo observations (with or without confirmed parentage) were identified for this variant in ClinVar or the literature.
PP1	Not assessed	No cosegregation data in affected family members is available for this variant.
PP2	Not assessed	PP2 requires a gene with a low rate of benign missense variation where missense is a common disease mechanism. FANCL constraint metrics (e.g., gnomAD missense Z-score) were not available, and the presence of missense variants at appreciable frequency in population databases (including homozygotes) does not clearly support a low benign missense rate.	gnomad_v2 gnomad_v4
PP3	Not met	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). HCI prior not available for FANCL.	revel bayesdel spliceai
PP4	Not assessed	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	Not met	No reputable source has classified this variant as pathogenic. ClinVar consensus across 6 clinical laboratory submissions is Uncertain significance. None of the ClinVar-associated PMIDs (GeneReviews, PDQ summaries, carrier screening guidelines, ACMG/Sherloc method papers) provide a variant-specific pathogenic classification.	clinvar
BA1	Not met	Allele frequency in all gnomAD populations is well below 1%. Highest subpopulation frequency is 0.165% (Middle Eastern, gnomAD v4.1).	gnomad_v2 gnomad_v4
BS1	Not met	Allele frequency does not exceed 0.3% in any gnomAD population. Highest subpopulation frequency is 0.165% (Middle Eastern, gnomAD v4.1).	gnomad_v2 gnomad_v4
BS2	Not assessed	While gnomAD v4.1 reports 2 homozygotes for this variant, the clinical status of these individuals is unknown. Without confirmation that these are healthy adults, BS2 (observed in a healthy adult for a fully penetrant early-onset disorder) cannot be applied.	gnomad_v4
BS3	Not assessed	No well-established functional studies demonstrating no damaging effect have been performed for this specific variant. OncoKB reports Unknown Oncogenic Effect with no variant-specific data.	oncokb
BS4	Not assessed	No segregation data are available to assess lack of cosegregation with disease in affected family members.
BP1	Not assessed	BP1 requires a gene where only truncating variants cause disease. FANCL has both missense and truncating variants reported in association with Fanconi anemia. Insufficient gene-level evidence to establish that missense variants in FANCL are not pathogenic.	pvs1_gene_context
BP2	Not assessed	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.
BP3	N/A	BP3 applies to in-frame deletions/insertions in repetitive regions; not applicable to a missense substitution.
BP4	Met	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 bayesdel spliceai
BP5	Not assessed	No data are available indicating this variant was found in a case with an alternative molecular basis for disease.
BP6	Not met	No reputable source has classified this variant as benign. ClinVar consensus across 6 clinical laboratory submissions is Uncertain significance.	clinvar
BP7	N/A	BP7 applies to silent (synonymous) variants with no predicted splice impact. This is a missense variant (c.238C>G, p.Leu80Val) and does not qualify.

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