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.1 This variant has been reported in ClinVar as Uncertain significance by two clinical laboratories (VariationID: 435127).2 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).3 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.4 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.5 No pathogenic or benign criteria are met under generic ACMG/AMP 2015 rules. The variant remains classified as a Variant of Uncertain Significance.6
FANCA
Final classification
VUS
FANCA c.2942G>C · p.Cys981Ser
FANCA
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.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: none; combination = no applied criteria, which maps to VUS.
Classification rationale
VUS
FANCA c.2942G>C
Gene diagram
· NM_000135.3 · variants mapped to exon structure
FANCA
NM_000135.3
Fetching transcript structure from UCSC…
Applied criteria · 0 applied · 22 assessed
Applied · 0
No criteria were applied for this variant.
Assessed · not applied
Pathogenic
PS1
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.
PS2
No de novo occurrence data was identified for NM_000135.3:c.2942G>C in any reviewed publication or database.
PS3
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.
PS4
No case-control or cohort data establishing significantly increased prevalence of NM_000135.3:c.2942G>C in affected individuals compared with controls.
PM1
Residue p.Cys981 does not lie in a statistically significant mutational hotspot per cancerhotspots.org.
PM2
Population frequency cannot be reliably assessed.
PM6
No de novo observation of NM_000135.3:c.2942G>C has been reported in any reviewed publication or database.
PP1
No cosegregation data with disease in multiple affected family members is available for this variant.
PP2
No HCI prior score is available for FANCA to assess missense constraint (gene not supported by HCI prior tool).
PP3
In silico predictions do not provide concordant evidence of a deleterious effect.
PP4
No patient phenotype or clinical data is available for the individuals carrying this variant.
PP5
No reputable source has reported NM_000135.3:c.2942G>C as pathogenic.
Benign
BA1
No population frequency data is available to assess whether allele frequency exceeds 1%.
BS1
No population frequency data is available to assess whether allele frequency exceeds 0.3%.
BS2
No observation of NM_000135.3:c.2942G>C in a homozygous state in a healthy adult has been reported.
BS3
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.
BS4
No segregation data is available to assess lack of cosegregation with disease.
BP1
While FANCA truncating variants are a known cause of Fanconi anemia (autosomal recessive), missense variants are also a recognized disease mechanism in this gene.
BP2
No observation of NM_000135.3:c.2942G>C in trans with a known pathogenic FANCA variant has been reported.
BP4
Multiple lines of computational evidence do not concordantly suggest no impact.
BP5
No evidence has been identified that FANCA-associated disease follows an alternate molecular mechanism inconsistent with a missense change at position 981.
BP6
No reputable source has reported NM_000135.3:c.2942G>C as benign.
N/A · 6
PVS1 · PM3 · PM4 · PM5 · BP3 · BP7
Research & evidence
Population frequency
v4.1
This variant is absent from gnomAD v4.1.
v2.1
This variant is absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories). (ClinVarID = 435127)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.09). REVEL score = 0.594. BayesDel score = 0.285232.
Functional
Unknown Oncogenic Effect
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. FANCA, a DNA repair protein, is infrequently altered in cancer.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
Triaged references · 6 PMIDs not cited in assessment
25741868 ↗
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
CLINVAR
19888064 ↗
ACOG Committee Opinion No. 442: Preconception and prenatal carrier screening for genetic diseases in individuals of Eastern European Jewish descent.
CLINVAR
26389258 ↗
Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Version.
CLINVAR