NM_018062.3:c.355G>A

FANCL · NP_060532.2:p.(Gly119Arg) · NM_018062.3

GRCh37: chr2:58449096 C>T · GRCh38: chr2:58221961 C>T

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.(Gly119Arg)

gnomAD AF

6.206330705572913e-07 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_018062.3:c.355G>A (p.Gly119Arg) is a missense variant in exon 5 of FANCL, a gene associated with autosomal recessive Fanconi anemia. PVS1 is not applicable as this is not a null variant.

This variant is extremely rare in population databases, with an allele frequency of 7.96e-06 (0.0008%) in gnomAD v2.1 and 6.21e-07 (0.00006%) in gnomAD v4.1, meeting PM2 at supporting level.

Multiple computational predictors (REVEL 0.104, BayesDel -0.400665, SpliceAI max delta 0.03) concordantly suggest a benign effect, meeting BP4 at supporting level.

The variant has been reported in ClinVar as uncertain significance by two clinical laboratories (ClinVar ID 653483). No pathogenic or benign assertions exist from expert panels.

Functional data, segregation analysis, de novo observations, case-control studies, and variant-specific literature are all absent for this variant. No publications among the seven reviewed mention NM_018062.3:c.355G>A.

The balanced evidence profile (PM2_supporting vs. BP4_supporting) results in a net score of zero, consistent with a classification of uncertain significance under ACMG/AMP 2015 generic rules.

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 (c.355G>A, p.Gly119Arg) located in exon 5 of FANCL. It does not fall into the PVS1 null-variant categories of nonsense, frameshift, or canonical ±1,2 splice consensus variants per ClinGen SVI PVS1 recommendations (PMC6185798). The generic PVS1 framework does not apply to this variant class.	pvs1_generic_framework pvs1_variant_assessment
PS1	N/A	No known pathogenic variant at amino acid position 119 with a different amino acid change has been identified in ClinVar, COSMIC, or the reviewed literature. Without a same-residue pathogenic comparator, PS1 cannot be applied.	clinvar pm5_candidates
PS2	Not met	No de novo observation of NM_018062.3:c.355G>A has been reported in any of the seven reviewed publications. No de novo data are present in ClinVar submissions.	clinvar
PS3	Not met	No functional studies of NM_018062.3:c.355G>A (p.Gly119Arg) were identified. OncoKB reports Unknown Oncogenic Effect with no variant-specific reviewed functional evidence. None of the seven reviewed publications contain functional data for this variant.	oncokb
PS4	Not met	No case-control or case-series data for NM_018062.3:c.355G>A have been reported. ClinVar contains two submissions, both classifying the variant as uncertain significance; neither provides affected-vs-control cohort data. The variant's prevalence in gnomAD (2/251,302 in v2.1) does not support a statistically significant enrichment in affected individuals.	clinvar gnomad_v2 gnomad_v4
PS5	Not met	No reputable source has classified NM_018062.3:c.355G>A as pathogenic. ClinVar reports uncertain significance from two clinical laboratories; no expert panel or professional society has asserted a pathogenic classification.	clinvar
PM1	Not met	This variant does not lie in a statistically significant mutational hotspot. The hotspots analysis found no enrichment at residue 119 or the surrounding region. No critical functional domain has been specifically implicated at this residue by the available evidence.
PM2	Met	NM_018062.3:c.355G>A is extremely rare in population databases. In gnomAD v2.1, the total allele frequency is 7.96e-06 (2/251,302 alleles; 0.0008%), and in gnomAD v4.1 the allele frequency is 6.21e-07 (1/1,611,258 alleles; 0.00006%). Both are well below the 0.1% PM2 threshold for generic ACMG/AMP. The variant is absent from gnomAD-Canada. The highest subpopulation frequency is in East Asian (v2.1: 0.0109%, 2/18,394).	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	Automated PM5 candidate search found zero same-residue comparator variants at amino acid position 119 with a different pathogenic missense change. Unable to confirm classic same-residue PM5 semantics.	pm5_candidates
PM6	Not met	No de novo observation of this variant has been reported. Neither ClinVar submissions nor the reviewed publications provide any de novo confirmation data.	clinvar
PP1	Not met	No segregation data are available for NM_018062.3:c.355G>A. None of the reviewed publications report familial cosegregation analysis for this variant.
PP2	Not met	FANCL is associated with Fanconi anemia, an autosomal recessive disorder where loss of function is a known disease mechanism. However, there are insufficient data to establish that FANCL has a low rate of benign missense variation and that missense variants are a common mechanism of disease. The HCI prior model does not support FANCL for custom PP2 scoring.
PP3	Not met	Multiple in silico predictors do not support a deleterious effect. REVEL score is 0.104 (below typical pathogenic thresholds of ≥0.5), BayesDel score is -0.400665 (negative, favoring benign), and SpliceAI predicts no splicing impact (max delta score = 0.03). These do not meet the threshold for PP3.	revel bayesdel spliceai
PP4	Not met	No specific phenotypic data are available for individuals harboring NM_018062.3:c.355G>A. None of the reviewed publications describe patients with this variant, and ClinVar submissions do not include condition labels or phenotype details.	clinvar
PP5	Not met	No reputable source has recently reported NM_018062.3:c.355G>A as pathogenic. ClinVar classifies it as uncertain significance (two clinical laboratories, criteria provided single submitter). The ClinVar-associated publications are gene-level overviews (GeneReviews, PDQ summaries, practice guidelines) that do not mention this specific variant.	clinvar
BA1	Not met	The allele frequency of NM_018062.3:c.355G>A is well below the 1% BA1 threshold. gnomAD v2.1 total AF is 7.96e-06 (0.0008%); gnomAD v4.1 total AF is 6.21e-07 (0.00006%). The variant is too rare to qualify as a common benign polymorphism.	gnomad_v2 gnomad_v4
BS1	Not met	The allele frequency is well below the 0.3% BS1 threshold for generic ACMG/AMP. gnomAD v2.1 total AF is 0.0008% and v4.1 AF is 0.00006%. Even the highest subpopulation frequency (East Asian in v2.1: 0.0109%) remains far below 0.3%.	gnomad_v2 gnomad_v4
BS2	Not met	No homozygous observations of this variant have been reported in gnomAD (v2.1: 0 homozygotes out of 251,302; v4.1: 0 homozygotes out of 1,611,258). No case-control data demonstrate presence in healthy controls at a frequency inconsistent with disease penetrance.	gnomad_v2 gnomad_v4
BS3	Not met	No functional studies demonstrating a neutral or benign effect of p.Gly119Arg have been identified. While computational predictors favor a benign effect (REVEL 0.104, BayesDel -0.400665), these constitute in silico evidence (BP4) rather than the well-established functional assay data required for BS3.	revel bayesdel
BS4	Not met	No segregation data are available for NM_018062.3:c.355G>A. Lack of cosegregation with disease cannot be assessed without family studies.
BP1	Not met	FANCL is associated with Fanconi anemia, an autosomal recessive disorder where loss of function is a known disease mechanism. However, BP1 requires that a gene be one for which primarily truncating variants cause disease. While LoF is supported in FANCL, missense variants can also be pathogenic in Fanconi anemia genes (as evidenced by known pathogenic missense variants in FANCA, FANCC, FANCG, BRCA2/FANCD1, etc.). There is insufficient evidence to assert that only truncating variants cause FANCL-related disease.	pvs1_gene_context
BP2	Not met	NM_018062.3:c.355G>A has not been observed in trans with a known pathogenic FANCL variant in any reviewed source. No phase information is available from gnomAD, ClinVar, or the reviewed literature.	clinvar
BP4	Met	Multiple lines of computational evidence suggest no impact on the gene product. REVEL score is 0.104 (well below typical pathogenic thresholds ≥0.5), BayesDel score is -0.400665 (negative, supporting a benign interpretation), and SpliceAI predicts no splicing impact (max delta score = 0.03, below the 0.1 threshold). Three independent in silico tools concordantly predict a benign or non-deleterious effect.	revel bayesdel spliceai
BP5	Not met	No case has been identified in which NM_018062.3:c.355G>A was observed alongside an alternate molecular basis for disease. No such data exist in the reviewed literature or ClinVar submissions.
BP6	Not met	No reputable source has classified NM_018062.3:c.355G>A as benign or likely benign. ClinVar reports uncertain significance from two clinical laboratories; no benign assertion exists from any expert panel or professional body.	clinvar
BP7	Not met	NM_018062.3:c.355G>A is a missense variant (p.Gly119Arg), not a synonymous or intronic variant. BP7 applies only to silent variants at non-conserved nucleotides with no predicted splice impact. This variant changes the amino acid and is therefore ineligible for BP7.

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