NM_018062.3:c.524C>T

FANCL · NP_060532.2:p.(Ala175Val) · NM_018062.3

GRCh37: chr2:58425745 G>A · GRCh38: chr2:58198610 G>A

Gene: FANCL Transcript: NM_018062.3

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

FANCL

Transcript

NM_018062.3

Protein

NP_060532.2:p.(Ala175Val)

gnomAD AF

2.2930293148304458e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

This variant is absent or extremely rare in large population cohorts: gnomAD v2.1 allele frequency 0.00389% (11/282,764 alleles) and v4.1 allele frequency 0.00229% (37/1,613,586 alleles), meeting PM2 at supporting level.

Multiple in silico predictors do not support a deleterious effect: REVEL score 0.089, BayesDel score -0.494, and SpliceAI predicts no splicing impact (max delta 0.04), meeting BP4 at supporting level.

The variant has been reported in ClinVar as Uncertain significance by 4 clinical laboratories and Likely benign by 1 clinical laboratory (ClinVar Variation ID: 898372). No expert panel classification is available.

The variant is a missense substitution (p.Ala175Val) and does not qualify for PVS1. No functional studies, segregation data, case-control comparisons, or de novo observations were identified for this variant.

Applying generic ACMG/AMP 2015 final combination rules (PMID:25741868): PM2_supporting and BP4_supporting provide conflicting lines of evidence with no other criteria met. The variant is classified as a Variant of Uncertain Significance (VUS).

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.Ala175Val); it does not fall into a null-variant bucket (nonsense, frameshift, or canonical ±1,2 splice consensus). PVS1 is not applicable per ClinGen SVI PVS1 recommendations (PMC6185798).	pvs1_generic_framework
PS1	Not assessed	No evidence of a different nucleotide change at codon 175 resulting in the same Ala175Val amino acid substitution that has been established as pathogenic.
PS2	Not assessed	No de novo data with confirmed maternity and paternity available for this variant.
PS3	Not met	No well-established functional studies demonstrating a damaging effect for NM_018062.3:c.524C>T were identified. No reviewed publication contained variant-specific functional data.
PS4	Not assessed	No case-control data or sufficient patient observations to assess whether the variant prevalence differs significantly between affected individuals and controls.
PS5	Not assessed	No alternative pathogenic missense variant at codon 175 identified for comparison via ClinVar.
PM1	Not met	The variant is not located in a known mutational hotspot or well-established critical functional domain. Hotspot analysis confirmed residue 175 is not statistically significant.
PM2	Met	This variant is present at very low frequency in population databases: gnomAD v2.1 allele frequency 0.00389% (11/282,764 alleles) and v4.1 allele frequency 0.00229% (37/1,613,586 alleles), both well below the 0.1% PM2 threshold. No homozygotes observed.	gnomad_v2 gnomad_v4
PM5	N/A	No same-residue comparator missense variants at Ala175 with established pathogenicity were identified. PM5 candidate search returned no qualified comparators.
PM6	Not assessed	No de novo observations (with or without confirmed parentage) available for this variant.
PP1	Not assessed	No co-segregation data available for this variant.
PP2	Not assessed	Insufficient data to determine whether FANCL has a low rate of benign missense variation and a preponderance of pathogenic missense variants, which would be required for PP2 application.
PP3	Not met	Multiple in silico predictors do not support a deleterious effect: REVEL score 0.089 (well below the 0.5 threshold for pathogenicity), BayesDel score -0.494 (negative, favoring benign), and SpliceAI predicts no splicing impact (max delta 0.04).	revel bayesdel spliceai
PP4	Not assessed	No patient-specific phenotype or family history data available for review.
PP5	Not met	No reputable source has reported this variant as pathogenic. ClinVar classification is Uncertain significance (4 clinical laboratories) and Likely benign (1 clinical laboratory); no expert panel classification available.	clinvar
BA1	Not met	The highest population allele frequency (gnomAD v2.1 European non-Finnish: 0.00697%) is far below the 1% threshold required for BA1.	gnomad_v2
BS1	Not met	The highest population allele frequency (0.00697%) is below the 0.3% threshold required for BS1.	gnomad_v2
BS2	Not met	No homozygous observations in gnomAD (v2.1: 0 homozygotes; v4.1: 0 homozygotes). The variant has not been observed in a healthy adult homozygous state.	gnomad_v2 gnomad_v4
BS3	Not assessed	No well-established functional studies demonstrating no damaging effect for this specific variant were identified.
BS4	Not assessed	No segregation data available for this variant.
BP1	Not assessed	While FANCL is a gene in which biallelic loss-of-function variants cause Fanconi anemia, insufficient data are available to determine that primarily truncating (rather than missense) variants are the established cause of disease, which is required to apply BP1 to this missense variant.	pvs1_gene_context
BP2	Not met	FANCL is associated with disease through biallelic loss-of-function variants, not exclusively through missense changes. BP2 applies only to genes where disease is exclusively caused by missense variants.	pvs1_gene_context
BP4	Met	Multiple lines of computational evidence suggest no damaging effect: REVEL score 0.089 (benign), BayesDel score -0.494 (benign), and SpliceAI predicts no splicing impact (max delta 0.04).	revel bayesdel spliceai
BP5	Not assessed	No alternative missense variant at codon 175 with a benign classification was identified in ClinVar.
BP6	Not met	One ClinVar submitter (Ambry Genetics) classifies this variant as Likely benign, but four other clinical laboratories classify it as Uncertain significance. The single-submitter Likely benign classification does not meet the BP6 threshold for a reputable source with strong evidence of benign impact.	clinvar
BP7	N/A	This is a missense variant (c.524C>T, p.Ala175Val), not a silent/synonymous variant. BP7 applies only to synonymous variants without predicted splicing impact.
BP3	N/A	Substitution variant; BP3 applies to in-frame indels only.
PM3	N/A	Pre-marked as skip; PM3 assessment deferred.
PM4	N/A	Substitution variant; PM4 applies to non-repeat in-frame deletions/insertions and stop-loss variants only.

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