NM_018062.3:c.2T>C

FANCL · NP_060532.2:p.(Met1?) · NM_018062.3

GRCh37: chr2:58468447 A>G · GRCh38: chr2:58241312 A>G

Gene: FANCL Transcript: NM_018062.3

Final call

VUS

PVS1 moderate PM2 supporting

Variant details

Gene

FANCL

Transcript

NM_018062.3

Protein

NP_060532.2:p.(Met1?)

gnomAD AF

3.469623446723932e-05 (v4.1)

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

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.

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.

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	Met	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.	pvs1_generic_framework pvs1_gene_context pvs1_variant_assessment
PS1	N/A	No known pathogenic variant at the same nucleotide position (c.2) with a different nucleotide change was identified.
PS2	Not met	No de novo observation reported for this variant in any accessible data source. No parental testing data available.
PS3	Not met	No variant-specific functional studies were identified. Reviewed full-text papers (PMID:26149689, PMID:30540754) discuss FANCL domain structure and function at the gene level but do not directly test NM_018062.3:c.2T>C. The OncoKB annotation of Likely Loss-of-function is a curated inference, not experimental functional data for this variant.
PS4	Not met	No case-control data or statistical enrichment analysis is available. ClinVar submissions reference this variant in individuals with Fanconi anemia and various cancers, but prevalence data in affected versus control populations is not available for independent verification.	clinvar
PS5	Not met	No evidence that this variant has been observed in trans with a known pathogenic variant in FANCL. No phase information available from any data source.
PM1	Not met	The variant is located at the initiation codon, a critical functional element. However, this evidence is already captured by PVS1 for this start-loss variant; applying PM1 would constitute double-counting. No independent missense mutational hotspot at this codon was identified.
PM2	Met	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 gnomad_v4 gnomad_canada
PM5	N/A	PM5 applies to novel missense variants at the same codon as a known pathogenic missense. This variant (c.2T>C) is a start-loss, not a missense, and no same-residue missense comparators were identified by the pm5_candidates pipeline.
PM6	Not met	No de novo observation reported. Same evidence basis as PS2.
PP1	Not met	No segregation data available for this variant.
PP2	N/A	PP2 applies to missense variants in genes with a low rate of benign missense variation and where missense is a common disease mechanism. This is a start-loss variant, not a missense.
PP3	Not met	In silico predictions are mixed and inconclusive. REVEL score is 0.212 (below the 0.5 damaging threshold), BayesDel score is 0.66 (above the 0.27 damaging threshold), and SpliceAI predicts no splicing impact (max delta = 0.0). No HCI prior score is available. Multiple predictors do not agree on a deleterious effect. Additionally, missense-focused predictors (REVEL) are not well-calibrated for start-loss variants.	revel bayesdel spliceai
PP4	Not met	ClinVar submissions report this variant in individuals with Fanconi anemia and various cancers. However, the specific patient phenotypes are not independently verifiable from the available evidence. Fanconi anemia has at least 22 genetic etiologies, so the phenotype is not highly specific for a single gene. Without primary clinical data, PP4 cannot be applied.	clinvar
PP5	Not met	ClinVar classifies this variant as Pathogenic (VariationID: 566870). However, the review status is 'criteria provided, single submitter' — not 3-star expert panel. Per PP5 application rules, supporting-level evidence requires a 3-star ClinVar expert panel review. This threshold is not met.	clinvar
BA1	Not met	gnomAD allele frequency (0.00478% v2.1, 0.00347% v4.1) is well below the 1% BA1 threshold.	gnomad_v2 gnomad_v4
BS1	Not met	gnomAD allele frequency (0.00478% v2.1, 0.00347% v4.1) is well below the 0.3% BS1 threshold.	gnomad_v2 gnomad_v4
BS2	Not met	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. gnomAD shows no homozygotes, and no control cohort data with phenotype annotation is available.	gnomad_v2 gnomad_v4
BS3	Not met	No functional studies demonstrating no damaging effect for this variant. Reviewed full-text papers do not contain experimental data testing c.2T>C specifically.
BS4	Not met	No segregation data available to assess lack of segregation with disease.
BP1	N/A	BP1 applies to missense variants in genes where primarily truncating variants cause disease. This is a start-loss variant, which is a truncating-type variant, not a missense.
BP2	Not met	No data on observation in trans with a pathogenic variant in FANCL, a recessive disorder. Without phase information, BP2 cannot be assessed.
BP4	Not met	In silico predictions are mixed. REVEL score 0.212 suggests no damaging effect, but BayesDel score 0.66 suggests a damaging effect, and SpliceAI shows no splicing impact. Multiple lines of computational evidence do not consistently suggest no impact on gene product. Consensus for benign prediction is not achieved.	revel bayesdel spliceai
BP5	Not met	No evidence of an alternate molecular basis for disease in a case carrying this variant.
BP6	Not met	ClinVar classifies this variant as Pathogenic, not benign. Additionally, the review status is 'criteria provided, single submitter' — not 3-star expert panel. BP6 cannot be applied when the reported classification is pathogenic and the review status does not meet the 3-star threshold.	clinvar
BP7	N/A	BP7 applies to synonymous (silent) variants with no predicted splice impact. This is a start-loss variant (c.2T>C, p.Met1?), not a synonymous variant.

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