NM_000135.3:c.2003G>T

FANCA · NP_000126.2:p.(Ser668Ile) · NM_000135.3

GRCh37: chr16:89839690 C>A · GRCh38: chr16:89773282 C>A

Gene: FANCA Transcript: NM_000135.3

Final call

VUS

PM2 moderate BP4 supporting benign

Variant details

Gene

FANCA

Transcript

NM_000135.3

Protein

NP_000126.2:p.(Ser668Ile)

gnomAD AF

3.224537440104217e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_000135.3:c.2003G>T (p.Ser668Ile) is a missense variant in FANCA, a gene associated with autosomal recessive Fanconi anemia. The variant is extremely rare in population databases with an allele frequency of 6.42×10⁻⁶ in gnomAD v2.1 and 3.22×10⁻⁶ in gnomAD v4.1, meeting PM2 (moderate).

Multiple in silico tools predict a benign effect: REVEL score 0.276, BayesDel score -0.261, and SpliceAI max delta 0.00, meeting BP4 (supporting benign).

The variant is classified as Uncertain significance in ClinVar (VCID 2161267) by four clinical laboratories with criteria provided but no expert panel review. No pathogenic assertion from a reputable source exists.

No functional studies, case-control data, segregation data, de novo observations, or variant-specific literature citations were identified for this variant. OncoKB reports Unknown Oncogenic Effect with no curated PMIDs.

The only applicable evidence criteria are PM2 (moderate, supporting pathogenicity) and BP4 (supporting benign). These offset each other, leaving the variant with no net evidence weight toward either pathogenic or benign classification. The variant remains a Variant of Uncertain Significance.

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
BP3	N/A	BP3 applies to in-frame deletions/insertions in a repetitive region without a known function. NM_000135.3:c.2003G>T is a missense substitution, not an in-frame indel.
PM3	N/A	PM3 applies to recessive disorders when a variant is detected in trans with a known pathogenic variant. No in-trans genotype data are available for this case.
PM4	N/A	PM4 applies to protein length changes due to in-frame deletions/insertions or stop-loss variants. NM_000135.3:c.2003G>T is a missense substitution, not a protein-length-altering variant.
PVS1	N/A	NM_000135.3:c.2003G>T is a missense variant (p.Ser668Ile). PVS1 is reserved for null variants (nonsense, frameshift, canonical splice ±1/2, initiation codon, single/multi-exon deletion) per the ClinGen SVI PVS1 decision tree (PMC6185798). This variant does not fall into any default null-variant bucket. No functional data exist demonstrating that this specific missense abolishes protein function to a null-equivalent degree.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	Not met	No evidence of a previously established pathogenic missense variant at the same amino acid position (Ser668) producing the same amino acid change (Ser668Ile) was identified in ClinVar, the literature, or any other source reviewed.	clinvar pm5_candidates
PS2	Not met	No de novo data are available for NM_000135.3:c.2003G>T in any source reviewed. No publication, ClinVar submission, or database entry reports a confirmed de novo occurrence of this variant.	clinvar oncokb
PS3	Not met	No functional experimental data were identified for NM_000135.3:c.2003G>T (p.Ser668Ile). OncoKB reports Unknown Oncogenic Effect with no associated PMIDs. None of the publications reviewed contain variant-specific functional assays. No systematic range characterization (tiling screen, saturation mutagenesis, truncation series) spanning residue 668 was identified.	oncokb
PS4	Not met	No case-control studies or case series demonstrating enrichment of NM_000135.3:c.2003G>T in affected individuals over controls were identified. The variant has not been reported in COSMIC (somatic cancers). ClinVar submissions are limited to clinical laboratory classifications of Uncertain significance without associated case-level phenotype data.	clinvar
PS5	Not met	No reputable source (expert panel, clinical practice guideline, or well-established laboratory) has reported NM_000135.3:c.2003G>T as definitively pathogenic. ClinVar classification is Uncertain significance from 4 clinical laboratories with criteria provided but no expert panel review.	clinvar
PM1	Not met	The variant does not lie in a statistically significant mutational hotspot as assessed by cancerhotspots.org (residue_significant=false). Residue 668 is not within a well-characterized functional domain with domain-specific evidence for PM1 in the materials reviewed. No domain-level functional characterization spanning residue 668 was identified in the literature.
PM2	Met	NM_000135.3:c.2003G>T is extremely rare in population databases. In gnomAD v2.1 exomes, the variant is observed at an allele frequency of 6.42×10⁻⁶ (1/155,698 alleles; MAF 0.00064%), far below the 0.1% threshold for PM2. In gnomAD v4.1, the AF is 3.22×10⁻⁶ (5/1,550,610 alleles; MAF 0.00032%). No homozygotes are reported in either dataset. The variant is absent from gnomAD-Canada. This ultra-rare population frequency supports a moderate evidence weight for pathogenicity under the ACMG/AMP framework.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not met	No pathogenic missense variant at the same amino acid residue (Ser668) with a different amino acid change was identified as a comparator. The automatic PM5 candidate harvest found no same-residue pathogenic variants in ClinVar. PM5 cannot be applied without a confirmed pathogenic comparator at the same residue.	pm5_candidates clinvar
PM6	Not met	No de novo occurrence of NM_000135.3:c.2003G>T has been reported with confirmed maternity and paternity. No publication or ClinVar submission describes this variant as a de novo event. PM6 cannot be applied without a documented de novo case.	clinvar
PP1	Not met	No segregation data are available for NM_000135.3:c.2003G>T. No publication or database record describes co-segregation of this variant with disease in a family. PP1 cannot be applied without segregation evidence.
PP2	Not met	PP2 requires a low rate of benign missense variation in the gene and demonstration that missense variants are a common disease mechanism. While FANCA missense variants can be pathogenic in Fanconi anemia, no gene-level missense constraint metric (e.g., gnomAD missense Z-score, missense o/e ratio) was available in the evidence materials to confirm a low rate of benign missense variation specifically for FANCA. PP2 cannot be applied without this quantitative constraint data.	gnomad_v2 gnomad_v4
PP3	Not met	Multiple lines of in silico computational evidence do not support a deleterious effect of this variant. REVEL predicts a benign score of 0.276 (below the 0.5 threshold). BayesDel predicts a benign score of -0.261 (negative scores indicate benign). SpliceAI predicts no splicing impact (max delta score = 0.00). The computational evidence consistently points toward a benign or tolerated substitution, so PP3 is not met.	revel bayesdel spliceai
PP4	Not met	No patient phenotype or clinical data specific to NM_000135.3:c.2003G>T are available. The ClinVar submissions list no specific condition labels or clinical features. No publication describes the phenotype of individuals carrying this variant. PP4 requires patient phenotype specificity, which cannot be assessed without clinical data.	clinvar
PP5	Not met	No reputable source has classified NM_000135.3:c.2003G>T as pathogenic. ClinVar reports Uncertain significance from 4 clinical laboratories. The ClinVar-associated PMIDs triaged for PP5 (20301575, 24121147, 26389210) are GeneReviews and policy guideline documents that do not mention this specific variant. No expert panel, clinical practice guideline, or well-established clinical laboratory has asserted pathogenicity for this variant.	clinvar
BA1	Not met	The gnomAD allele frequency of NM_000135.3:c.2003G>T is 6.42×10⁻⁶ (v2.1) and 3.22×10⁻⁶ (v4.1), far below the 1% BA1 threshold. This is an ultra-rare variant, not a common polymorphism, so BA1 (stand-alone benign) does not apply.	gnomad_v2 gnomad_v4
BS1	Not met	The gnomAD allele frequency (6.42×10⁻⁶) is far below the 0.3% BS1 threshold. The variant is too rare in population databases to support a strong benign classification based on allele frequency.	gnomad_v2 gnomad_v4
BS2	Not met	No data are available regarding observation of NM_000135.3:c.2003G>T in healthy adult individuals. BS2 requires documented observation in trans with a pathogenic variant (for recessive disorders) or in a healthy adult with full penetrance expected at an early age (for dominant disorders). No such evidence exists in the reviewed materials.
BS3	Not met	No functional experimental data exist demonstrating that NM_000135.3:c.2003G>T (p.Ser668Ile) has no deleterious effect on protein function or splicing. No well-established in vitro or in vivo functional studies showing a benign effect were identified.	oncokb
BS4	Not met	No segregation data are available to assess lack of segregation with disease. BS4 requires observation that the variant does not segregate with the phenotype in affected family members, which cannot be evaluated without family-based genetic data.
BP1	Not met	BP1 applies to missense variants in genes where primarily truncating variants cause disease. FANCA is associated with Fanconi anemia, and missense variants are a well-established pathogenic mechanism in this gene. Both truncating and missense pathogenic variants are reported in ClinVar and the literature for FANCA, so the BP1 premise (primarily truncating mechanism) is not satisfied.	clinvar pvs1_gene_context
BP2	Not met	No data are available regarding observation of NM_000135.3:c.2003G>T in trans with a known pathogenic variant in FANCA (relevant for recessive Fanconi anemia) or in cis with a pathogenic variant. BP2 cannot be applied without genotype phasing data.
BP4	Met	Multiple lines of computational evidence suggest NM_000135.3:c.2003G>T (p.Ser668Ile) has no deleterious impact. REVEL predicts a benign score of 0.276 (well below the 0.5 threshold commonly used for pathogenic prediction). BayesDel predicts a benign score of -0.261 (negative scores indicate benign). SpliceAI predicts no splicing alteration (max delta score = 0.00). The concordance of multiple in silico predictors supports a supporting benign evidence weight.	revel bayesdel spliceai
BP5	Not met	No case has been identified where NM_000135.3:c.2003G>T is observed in an individual with an alternate molecular basis for disease. BP5 requires a documented case where the variant is present but another pathogenic variant explains the phenotype, and no such evidence exists in the reviewed materials.
BP6	Not met	No reputable source has classified NM_000135.3:c.2003G>T as benign. ClinVar classification is Uncertain significance from 4 clinical laboratories. BP6 requires a reputable source (e.g., expert panel, clinical practice guideline) to report the variant as benign, and no such assertion exists.	clinvar
BP7	N/A	BP7 applies to synonymous (silent) variants and intronic variants outside of conserved splice sites for which splicing prediction algorithms predict no impact. NM_000135.3:c.2003G>T is a missense variant producing p.Ser668Ile, not a synonymous or intronic variant. BP7 is not applicable to missense variants.

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