NM_000135.3:c.2942G>C

FANCA · NP_000126.2:p.(Cys981Ser) · NM_000135.3

GRCh37: chr16:89825024 C>G · GRCh38: chr16:89758616 C>G

Gene: FANCA Transcript: NM_000135.3

Final call

VUS

Variant details

Gene

FANCA

Transcript

NM_000135.3

Protein

NP_000126.2:p.(Cys981Ser)

gnomAD AF

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_000135.3:c.2942G>C (p.Cys981Ser) is a missense variant in FANCA, a gene in which loss-of-function is an established mechanism for autosomal recessive Fanconi anemia.

This variant has been reported in ClinVar as Uncertain significance by two clinical laboratories (VariationID: 435127).

Population frequency cannot be reliably assessed, as gnomAD v2.1 and v4.1 return no coverage data at this genomic position, and gnomAD-Canada v1.0 shows zero individuals called (AN=0).

In silico predictions are mixed: SpliceAI predicts no splice impact (max delta 0.09), BayesDel is in the benign range (0.285), and REVEL is intermediate (0.594). No computational tool provides a strong prediction in either direction.

No variant-specific functional studies, segregation data, de novo observations, or case-control data have been identified for this variant. The variant does not lie in a statistically significant mutational hotspot.

No pathogenic or benign criteria are met under generic ACMG/AMP 2015 rules. The variant remains classified as 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
PVS1	N/A	NM_000135.3:c.2942G>C is a missense variant (p.Cys981Ser) and does not fall into the default generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants. The generic PVS1 decision framework explicitly returned apply_generic_pvs1_framework: false.	pvs1_variant_assessment pvs1_generic_framework
PS1	Not met	No evidence that a different nucleotide change at the same codon (c.2942) resulting in the same amino acid change (p.Cys981Ser) has been established as pathogenic. This criterion requires a known pathogenic missense variant at the same position arising from a different nucleotide substitution.
PS2	Not met	No de novo occurrence data was identified for NM_000135.3:c.2942G>C in any reviewed publication or database. Neither paternity nor maternity confirmation data is available.
PS3	Not met	No well-established in vitro or in vivo functional studies have been identified for NM_000135.3:c.2942G>C (p.Cys981Ser) or for a systematically characterized range that includes this residue. OncoKB reports 'Unknown Oncogenic Effect' with no variant-specific functional evidence. No publication in the literature packet reports functional data for this variant.	oncokb
PS4	Not met	No case-control or cohort data establishing significantly increased prevalence of NM_000135.3:c.2942G>C in affected individuals compared with controls. The ClinVar submissions do not provide affected-vs-control prevalence statistics.	clinvar
PS5	Not met	No reputable source has recently reported NM_000135.3:c.2942G>C as pathogenic. ClinVar classification is Uncertain significance (2 clinical laboratories, criteria provided, single submitter).	clinvar
PM1	Not met	Residue p.Cys981 does not lie in a statistically significant mutational hotspot per cancerhotspots.org. No publication in the literature packet establishes position 981 as a critical functional domain residue. Without domain-level characterization or hotspot data, PM1 cannot be applied.
PM2	Not met	Population frequency cannot be reliably assessed. gnomAD v2.1 and v4.1 returned null data at this genomic position (16-89825024-C-G hg19 / 16-89758616-C-G hg38), indicating lack of coverage rather than confirmed absence. gnomAD-Canada v1.0 shows AN=0 (no individuals called at this position). Without interpretable population frequency data, PM2 (absent from controls, AF < 0.1%) cannot be confirmed. A ClinVar submission (SCV002269253, Invitae) asserts absence from ExAC, but this cannot be independently verified through available gnomAD data.	gnomad_v2 gnomad_v4 gnomad_canada clinvar
PM5	N/A	Unable to confirm classic same-residue PM5 semantics; automatic candidate harvesting found no same-residue comparator variants with a different pathogenic missense change at codon 981.	pm5_candidates
PM6	Not met	No de novo observation of NM_000135.3:c.2942G>C has been reported in any reviewed publication or database. No confirmation of paternity and maternity is available.
PP1	Not met	No cosegregation data with disease in multiple affected family members is available for this variant. No family studies were identified in the literature packet.
PP2	Not met	No HCI prior score is available for FANCA to assess missense constraint (gene not supported by HCI prior tool). Without quantified evidence that FANCA has a low rate of benign missense variation and that missense variants are a common mechanism of disease, PP2 cannot be applied under generic ACMG.
PP3	Not met	In silico predictions do not provide concordant evidence of a deleterious effect. REVEL score is 0.594 (intermediate, below typical 0.75 threshold), BayesDel is 0.285 (below damaging threshold), and SpliceAI max delta is 0.09 (no predicted splice impact). The computational evidence is mixed and does not meet the threshold for PP3.	revel bayesdel spliceai
PP4	Not met	No patient phenotype or clinical data is available for the individuals carrying this variant. The ClinVar submissions report 'not specified' or no condition labels, providing no phenotype specificity information.	clinvar
PP5	Not met	No reputable source has reported NM_000135.3:c.2942G>C as pathogenic. ClinVar consensus is Uncertain significance. The ClinVar-associated PMIDs (18197057, 19888064, 26389210, 26389258, 26389333) are general carrier screening guidelines or PDQ cancer genetics summaries that do not mention this specific variant.	clinvar
BA1	Not met	No population frequency data is available to assess whether allele frequency exceeds 1%. gnomAD v2.1 and v4.1 return null data (no coverage) at this genomic position. BA1 requires a confirmed allele frequency > 1% in a general population database.	gnomad_v2 gnomad_v4
BS1	Not met	No population frequency data is available to assess whether allele frequency exceeds 0.3%. gnomAD returns null data at this position. BS1 cannot be applied without interpretable frequency data.	gnomad_v2 gnomad_v4
BS2	Not met	No observation of NM_000135.3:c.2942G>C in a homozygous state in a healthy adult has been reported. gnomAD data is unavailable; no homozygous calls have been identified.
BS3	Not met	No well-established in vitro or in vivo functional studies demonstrate no damaging effect of NM_000135.3:c.2942G>C on protein function or splicing. No functional data was identified for this variant.
BS4	Not met	No segregation data is available to assess lack of cosegregation with disease. No family studies were identified.
BP1	Not met	While FANCA truncating variants are a known cause of Fanconi anemia (autosomal recessive), missense variants are also a recognized disease mechanism in this gene. BP1 (missense variant in a gene where primarily truncating variants cause disease) does not apply because pathogenic missense variants are documented in FANCA.	pvs1_gene_context
BP2	Not met	No observation of NM_000135.3:c.2942G>C in trans with a known pathogenic FANCA variant has been reported. No phase data is available.
BP4	Not met	Multiple lines of computational evidence do not concordantly suggest no impact. While SpliceAI predicts no splicing effect (max delta 0.09) and BayesDel is in the benign range (0.285), REVEL score is 0.594 which is in an intermediate range and does not support a benign classification. The evidence is not uniformly benign; BP4 requires concordant benign predictions.	revel bayesdel spliceai
BP5	Not met	No evidence has been identified that FANCA-associated disease follows an alternate molecular mechanism inconsistent with a missense change at position 981. This criterion would require a specific observation that the disease mechanism excludes the variant type in question, which has not been demonstrated.
BP6	Not met	No reputable source has reported NM_000135.3:c.2942G>C as benign. ClinVar classification is Uncertain significance, not benign.	clinvar
BP7	N/A	NM_000135.3:c.2942G>C is a missense variant (p.Cys981Ser), not a synonymous or intronic variant. BP7 applies only to synonymous variants with no predicted splice impact.
BP3	N/A	NM_000135.3:c.2942G>C is a single-nucleotide missense substitution, not an in-frame insertion or deletion.
PM3	N/A	Not assessed for this case as specified in the skip list.
PM4	N/A	Not assessed for this case as specified in the skip list.

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