NM_018062.3:c.1A>G

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

GRCh37: chr2:58468448 T>C · GRCh38: chr2:58241313 T>C

Gene: FANCL Transcript: NM_018062.3

Final call

VUS

PVS1 moderate PM2 supporting PP5 supporting

Variant details

Gene

FANCL

Transcript

NM_018062.3

Protein

NP_060532.2:p.(Met1?)

gnomAD AF

3.717241806579518e-06 (v4.1)

ClinVar

Likely pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_018062.3:c.1A>G (p.Met1Val) is an initiation codon variant in FANCL, where loss-of-function is an established mechanism for autosomal recessive Fanconi anemia. The variant abolishes the initiator methionine with no alternative start codon in exon 1, qualifying for PVS1 at moderate strength per ClinGen SVI recommendations (PMC6185798).

The variant is absent from gnomAD v2.1 (0/250,782 alleles) and present at extremely low frequency in gnomAD v4.1 (AF=0.00037%, 6/1,614,100 alleles, no homozygotes), meeting PM2 at supporting strength.

Two clinical laboratories have independently classified this variant as Likely pathogenic and Pathogenic in ClinVar (Variation ID 1691887, 2-star review status), satisfying PP5 at supporting strength. However, full-text review of the PMIDs cited in these ClinVar submissions did not confirm variant-specific evidence.

No variant-specific functional studies (PS3), de novo observations (PS2/PM6), segregation data (PP1), or case-control data (PS4) were identified for this variant in the reviewed literature.

The ACMG/AMP evidence tally of 1 moderate (PVS1) and 2 supporting (PM2, PP5) criteria does not reach the Likely Pathogenic threshold (requires 1 moderate + 4 supporting or 2 moderate + 2 supporting). This variant is classified as a Variant of Uncertain Significance (VUS) by formal ACMG/AMP 2015 combination rules, bordering on Likely Pathogenic given the initiation codon loss mechanism and concordant clinical laboratory classifications.

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	c.1A>G is an initiation codon variant (ATG>GTG, p.Met1Val) in FANCL, a gene where loss-of-function is an established disease mechanism for Fanconi anemia. No alternative in-frame ATG start codon is present in exon 1 (residues 1-32: MAVTEASLLRQCPLLLPQNRSKTVYEGFISAQ). Per ClinGen SVI PVS1 recommendations (PMC6185798), initiation codon variants without an alternative start codon in the same exon qualify for PVS1 at moderate strength. The pipeline-generated pvs1_variant_assessment incorrectly assigned this variant to the 'other' bucket; this adjudication overrides that assignment because c.1A>G is unequivocally a start codon loss, which is an ACMG-recognized null variant type.	pvs1_generic_framework pvs1_gene_context pvs1_variant_assessment PMID:25741868 PMID:25754594 PMID:30540754
PS1	N/A	PS1 applies to same amino acid change as an established pathogenic missense variant. This is an initiation codon loss variant (p.Met1Val), not a standard missense; the initiation codon loss mechanism is fundamentally distinct and not amenable to PS1 comparison.
PS2	Not met	No de novo observation of NM_018062.3:c.1A>G has been reported in the literature. None of the reviewed publications document a de novo occurrence with confirmed paternity and maternity.
PS3	Not met	No variant-specific functional studies were identified. Full-text review of seven publications and abstract review of eight additional publications returned no direct experimental characterization of NM_018062.3:c.1A>G. The ClinVar submission from Labcorp Genetics (SCV005703968) acknowledges that 'functional studies have not been performed to directly test the effect of this variant on FANCL protein function.' OncoKB classifies as 'Likely Loss-of-function' computationally and cites zebrafish gene-level knockout studies (PMID:20661450, PMID:30540754) and FANCL domain structural studies (PMID:26149689), none of which tested this specific variant. Domain-level inference from these papers supports PM1-type reasoning but does not satisfy PS3's requirement for variant-specific experimental data.	clinvar oncokb
PS4	Not met	No case-control or cohort data comparing the prevalence of NM_018062.3:c.1A>G in affected individuals versus the general population has been published. The variant is present at extremely low frequency in gnomAD (0.00037%), but there is no statistically powered comparison in an affected cohort.	gnomad_v4
PS5	N/A	PS5 requires an established pathogenic missense variant at the same codon with a different amino acid change. The initiation codon (ATG) is fundamentally distinct from standard missense codons; no alternative pathogenic initiation codon variant has been established at codon 1 of FANCL. This criterion is not applicable to start codon loss variants.
PM1	Not met	The variant affects the initiator methionine at the very N-terminus of FANCL. While the start codon is critical for protein expression, cancerhotspots.org reports no statistically significant hotspot at this residue. FANCL contains three well-characterized functional domains (E2-like fold/ELF at N-terminus, DRWD central domain, RING C-terminal domain), but the initiation codon itself does not lie within a domain region characterized by an excess of pathogenic missense variants. The loss of all protein domains resulting from start codon loss is more appropriately captured by PVS1 than by PM1 domain-level criteria.	PMID:26149689
PM2	Met	NM_018062.3:c.1A>G is absent from gnomAD v2.1 (0/250,782 alleles) and present at extremely low frequency in gnomAD v4.1 (AF=0.00037%, 6/1,614,100 alleles, no homozygotes). The maximum observed subpopulation frequency is in European (non-Finnish) at 0.00051% (6/1,180,000). The grpmax filtering allele frequency (FAF) is 1.83e-06. All frequencies are well below the PM2 threshold of <0.1%. The variant is also absent from gnomAD-Canada v1.0. Assigned supporting rather than moderate strength due to trace presence (6 alleles) in gnomAD v4.1.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	Unable to identify a classic same-residue missense comparator for PM5 evaluation. The protein consequence p.(Met1?) does not resolve to a standard missense amino acid change at a defined residue position. The automated pm5_candidates pipeline confirmed this and recommended against applying PM5. No alternative pathogenic missense at codon 1 of FANCL has been identified.	pm5_candidates
PM6	Not met	No de novo confirmation of NM_018062.3:c.1A>G has been reported in the literature. None of the reviewed publications include trio-based sequencing data demonstrating a de novo occurrence of this variant.
PP1	Not met	No segregation data are available for NM_018062.3:c.1A>G. None of the reviewed publications report co-segregation of this variant with disease in affected family members.
PP2	Not met	FANCL disease mechanism is loss-of-function, not missense-predominant. The variant is a start codon loss (functionally null), not a standard missense. PP2 is designed for missense variants in genes where missense is a common disease mechanism; FANCL pathogenicity is predominantly driven by truncating/null variants.	PMID:25754594
PP3	Not met	REVEL score 0.227 falls below the typical pathogenic threshold (>0.5). BayesDel score -0.184843 is negative, predicting benign. SpliceAI max delta score is 0.00, predicting no splicing impact. However, standard in silico missense predictors (REVEL, BayesDel) are not calibrated for initiation codon loss variants; their scores do not reliably predict the functional consequence of abolishing translation initiation. HCI prior probability is not available for FANCL. Multiple lines of in silico evidence do not converge on a pathogenic prediction for this variant type.	revel bayesdel spliceai
PP4	Not met	While Fanconi anemia is a highly specific clinical syndrome, its genetic etiology involves at least 22 genes (FANCA through FANCW). PP4 requires a highly specific phenotype for a disease with a single genetic etiology; Fanconi anemia is genetically heterogeneous and does not meet this criterion. No patient-specific phenotype data were available in the case materials for independent evaluation.	clinvar
PP5	Met	Two clinical diagnostic laboratories have independently classified NM_018062.3:c.1A>G as likely pathogenic or pathogenic in ClinVar (Variation ID: 1691887; VCV001691887). Labcorp Genetics/Invitae (SCV005703968) classifies as Pathogenic with criteria provided (citing PM2, PS3). Fulgent Genetics (SCV005658736) classifies as Likely pathogenic (clinical testing). The ClinVar aggregate classification is Pathogenic/Likely pathogenic with review status 'criteria provided, multiple submitters, no conflicts' (2 stars). However, these classifications are from single submitters without expert panel review, and the evidence underlying the cited criteria is not independently verifiable from the case materials. Full-text review of the cited PMIDs did not confirm variant-specific evidence. Assigned supporting strength per ACMG/AMP PP5 guidance for reputable source reporting without independent verification.	clinvar PMID:26149689 PMID:29335925 PMID:29625052
BA1	Not met	The maximum allele frequency of NM_018062.3:c.1A>G in gnomAD is 0.00051% (European non-Finnish, v4.1), far below the BA1 threshold of >1%. The variant is absent from gnomAD v2.1 and gnomAD-Canada.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	The maximum allele frequency of NM_018062.3:c.1A>G in gnomAD is 0.00051% (European non-Finnish, v4.1), far below the BS1 threshold of >0.3%.	gnomad_v2 gnomad_v4
BS2	Not met	No observation of NM_018062.3:c.1A>G in a healthy adult individual has been documented outside of population databases. The 6 heterozygous carriers in gnomAD v4.1 lack phenotype data and cannot be confirmed as healthy adults with full penetrance age.	gnomad_v4
BS3	Not met	No well-established in vitro or in vivo functional studies demonstrate that NM_018062.3:c.1A>G has no deleterious effect on protein function or splicing. OncoKB computationally classifies the variant as 'Likely Loss-of-function,' which is contrary to a benign interpretation. No experimental data support a benign functional outcome for this initiation codon loss.	oncokb
BS4	Not met	No lack of segregation data has been reported for NM_018062.3:c.1A>G. BS4 requires documented non-segregation with disease in affected family members, which is absent from the literature.
BP1	N/A	BP1 applies specifically to missense variants in genes where primarily truncating variants are known to cause disease. NM_018062.3:c.1A>G is an initiation codon loss variant, functionally equivalent to a null/truncating variant rather than a standard missense. The disease mechanism for FANCL is loss-of-function through truncating/null variants, consistent with this variant's predicted effect. BP1 is not applicable to null variants.
BP2	Not met	No evidence demonstrates that NM_018062.3:c.1A>G has been observed in trans with a known pathogenic FANCL variant in a healthy individual. No phase-resolved genotype data are available.
BP4	Not met	While BayesDel (-0.184843) and REVEL (0.227) scores are low and SpliceAI predicts no splicing impact (delta 0.00), these in silico tools are designed and calibrated for standard missense variants. They are not validated for predicting the functional consequence of initiation codon loss variants, which operate through a fundamentally different mechanism (abolition of translation initiation rather than amino acid substitution effect). The computational scores do not constitute reliable evidence that the variant has no impact on the gene product.	revel bayesdel spliceai
BP5	Not met	No observation of NM_018062.3:c.1A>G in a case where an alternative molecular basis for disease was identified has been reported. BP5 requires documented co-occurrence with an alternative pathogenic variant explaining the phenotype.
BP6	Not met	No reputable source classifies NM_018062.3:c.1A>G as benign or likely benign. ClinVar reports Pathogenic/Likely pathogenic from two clinical laboratories. OncoKB classifies as Likely Oncogenic. All available curated sources indicate a pathogenic or likely pathogenic interpretation.	clinvar oncokb
BP7	N/A	BP7 applies to synonymous variants with no predicted splice impact. NM_018062.3:c.1A>G is a non-synonymous initiation codon change (p.Met1Val), not a synonymous variant. BP7 is not applicable.

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