NM_018062.3:c.233C>G

FANCL · NP_060532.2:p.(Pro78Arg) · NM_018062.3

GRCh37: chr2:58453903 G>C · GRCh38: chr2:58226768 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.(Pro78Arg)

gnomAD AF

4.960132931562566e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

This missense variant (c.233C>G, p.Pro78Arg) in FANCL is absent from gnomAD v2.1 and present at extremely low frequency in gnomAD v4.1 (AF=0.000496%, 8/1,612,860 alleles, no homozygotes), meeting PM2 at supporting strength.

Multiple lines of computational evidence (REVEL 0.105, BayesDel -0.364706, SpliceAI max delta 0.04) suggest no damaging impact on the gene product, meeting BP4 at supporting benign strength.

This variant has been reported in ClinVar as Uncertain significance by two clinical laboratories with no expert panel classification; no case-control, functional, or segregation data specific to this variant were identified.

With one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4), the evidence is balanced and the variant is classified as Uncertain significance per ACMG/AMP 2015 combination rules (PMID:25741868).

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 missense variant (c.233C>G, p.Pro78Arg) does not fall into the default generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants per ClinGen SVI PVS1 recommendations (PMC6185798).	pvs1_variant_assessment pvs1_generic_framework
PS1	Not assessed	No data available on other missense variants at the same amino acid position (Pro78) with an established pathogenic classification.
PS2	Not assessed	No de novo occurrence data available for this variant.
PS3	Not met	No variant-specific functional studies were identified. OncoKB reports Unknown Oncogenic Effect for this variant. In silico predictors REVEL (0.105) and BayesDel (-0.364706) do not support a damaging functional effect.	oncokb revel bayesdel
PS4	Not met	No case-control studies demonstrating significantly increased prevalence of this variant in affected individuals compared to controls were identified. The variant is reported in ClinVar only as Uncertain significance by two clinical laboratories.	clinvar
PS5	Not assessed	No data on this variant observed in trans with a known pathogenic variant.
PM1	Not met	This variant does not lie in a statistically significant mutational hotspot. Residue Pro78 is not in a well-characterized functional domain with enrichment of pathogenic missense variants in FANCL.
PM2	Met	This variant is absent from gnomAD v2.1 and present at extremely low frequency in gnomAD v4.1 (global AF=0.000496%, 8/1,612,860 alleles, no homozygotes; grpmax FAF=1.065e-05), meeting the PM2 threshold of <0.1% for a rare variant.	gnomad_v2 gnomad_v4
PM5	N/A	Unable to confirm classic same-residue PM5 semantics; no pathogenic missense variants identified at the same amino acid residue (Pro78) for comparison.	pm5_candidates
PM6	Not assessed	No de novo occurrence data available for this variant.
PP1	Not assessed	No cosegregation data available for this variant.
PP2	Not assessed	HCI prior data are not available for FANCL; unable to assess the rate of benign missense variation in this gene relative to disease-causing missense variants.
PP3	Not met	Multiple in silico tools predict a benign effect: REVEL score 0.105 (below the commonly used 0.5 threshold), BayesDel score -0.364706 (negative score supports benign), and SpliceAI max delta score 0.04 (no predicted splicing impact).	revel bayesdel spliceai
PP4	Not assessed	No patient phenotype or family history data available for assessment.
PP5	Not met	This variant is classified as Uncertain significance in ClinVar by two clinical laboratories (review status: criteria provided, single submitter). No reputable source has classified this variant as pathogenic.	clinvar
BA1	Not met	This variant has a global allele frequency of 0.000496% in gnomAD v4.1 (grpmax FAF=1.065e-05), well below the BA1 threshold of >1%.	gnomad_v4
BS1	Not met	This variant has a global allele frequency of 0.000496% in gnomAD v4.1 (grpmax FAF=1.065e-05), below the BS1 threshold of >0.3% for a disorder of this prevalence.	gnomad_v4
BS2	Not assessed	No data on observation of this variant in healthy adults beyond population database representation.
BS3	Not assessed	No variant-specific functional studies demonstrating no damaging effect on protein function or splicing were identified.
BS4	Not assessed	No nonsegregation data available for this variant.
BP1	N/A	FANCL is associated with Fanconi anemia, where both missense and loss-of-function variants are established disease mechanisms. BP1 applies only to genes where primarily truncating variants cause disease.	pvs1_gene_context
BP2	Not assessed	No data on this variant observed in trans with a pathogenic variant in FANCL, which would be expected for a recessive disorder.
BP4	Met	Multiple lines of computational evidence suggest no impact on the gene product: REVEL score 0.105, BayesDel score -0.364706, and SpliceAI max delta score 0.04 (no predicted splicing impact).	revel bayesdel spliceai
BP5	Not assessed	No data on this variant observed in a case with an alternate molecular basis for disease.
BP6	Not met	This variant is classified as Uncertain significance in ClinVar by two clinical laboratories; no reputable source has classified this variant as benign.	clinvar
BP7	N/A	BP7 applies to synonymous variants with no predicted splicing impact. This is a missense variant (c.233C>G, p.Pro78Arg) and does not qualify.

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.