About FANCA
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
FANCA c.2942G>C, p.(Cys981Ser)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 0
Benign evidence criteria: 0
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
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.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
No screenshot for this evidence
Population frequency
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
No listed criterion applied
SpliceAI score
0.090 maximum delta
Recorded SpliceAI maximum delta score: 0.090. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
2 reported laboratory submissions
2 Uncertain significance. ClinVar API review status: criteria provided, multiple submitters, no conflicts.
Context only
ClinVar ↗
Functional evidence
Statement recorded
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.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
29 criteria with recorded statuses: 0 met · 23 not met · 0 not assessed · 6 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
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.
No criteria match.
Not met · 23 · evaluated, threshold not reached
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. This criterion requires a known pathogenic missense variant at the same position arising from a different nucleotide substitution. Details ▾Hide ▴
Evidence considered
- No same-amino-acid
- different-nucleotide pathogenic variant identified at this codon.
Still missing
- No systematic search for same-residue pathogenic variants with different nucleotide changes.
PS2 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. Details ▾Hide ▴
Evidence considered
- No de novo observation reported in ClinVar
- literature
- or databases.
Still missing
- No parental testing data available.
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. OncoKB reports 'Unknown Oncogenic Effect' with no variant-specific functional evidence. No publication in the literature packet reports functional data for this variant. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect
- no variant-specific functional evidence. No functional data in literature.
Still missing
- No functional studies exist for this variant or a systematically characterized range including position 981.
Sources
PS4 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. Details ▾Hide ▴
Evidence considered
- ClinVar reports 2 clinical laboratory submissions
- both VUS
- no prevalence data provided.
Still missing
- No case-control or cohort prevalence data.
Sources
PM1 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. Details ▾Hide ▴
Evidence considered
- cancerhotspots.org: no significant hotspot at this residue. No domain-level functional characterization in literature.
Still missing
- No domain-level characterization data for position 981 in FANCA.
PM2 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. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: null (no coverage)
- gnomAD v4.1: null (no coverage)
- gnomAD-Canada: AC=0
- AN=0 (no coverage)
- ClinVar SCV002269253 asserts ExAC absence but not independently verifiable.
Still missing
- Reliable population frequency data is unavailable for this genomic position
- gnomAD coverage at this locus is absent.
Sources
PM6 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. Details ▾Hide ▴
Evidence considered
- No de novo observation reported.
Still missing
- No parental testing or de novo data available.
PP1 No cosegregation data with disease in multiple affected family members is available for this variant. No family studies were identified in the literature packet. Details ▾Hide ▴
Evidence considered
- No cosegregation data available.
Still missing
- No family studies or segregation analysis available.
PP2 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. Details ▾Hide ▴
Evidence considered
- HCI prior not available for FANCA (gene_not_supported).
Still missing
- Missense constraint metric not available for FANCA.
PP3 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. Details ▾Hide ▴
Evidence considered
- REVEL: 0.594 (intermediate/borderline)
- BayesDel: 0.285 (benign range)
- SpliceAI max delta: 0.09 (no splice impact).
Sources
PP4 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. Details ▾Hide ▴
Evidence considered
- ClinVar submissions lack specific phenotype data
- condition labels absent or 'not specified'.
Still missing
- No patient phenotype data available to assess phenotypic specificity.
Sources
PP5 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. Details ▾Hide ▴
Evidence considered
- ClinVar: Uncertain significance
- no pathogenic assertion. Associated publications are general guidelines
- not variant-specific reports.
Sources
BA1 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. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 and v4.1: no frequency data available (null coverage).
Still missing
- Population frequency data unavailable.
Sources
BS1 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. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 and v4.1: no frequency data available (null coverage).
Still missing
- Population frequency data unavailable.
Sources
BS2 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. Details ▾Hide ▴
Evidence considered
- No homozygous observation in healthy individuals reported.
Still missing
- No homozygous genotype data available.
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. No functional data was identified for this variant. Details ▾Hide ▴
Evidence considered
- No functional studies identified.
Still missing
- No functional data available.
BS4 No segregation data is available to assess lack of cosegregation with disease. No family studies were identified. Details ▾Hide ▴
Evidence considered
- No segregation data available.
Still missing
- No family studies or segregation analysis available.
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. BP1 (missense variant in a gene where primarily truncating variants cause disease) does not apply because pathogenic missense variants are documented in FANCA. Details ▾Hide ▴
Evidence considered
- FANCA loss-of-function is a known disease mechanism
- but missense variants are also pathogenic
- BP1 not applicable.
Sources
pvs1_gene_context
BP2 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. Details ▾Hide ▴
Evidence considered
- No observation in trans with a pathogenic variant.
Still missing
- No phase data available.
BP4 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. Details ▾Hide ▴
Evidence considered
- SpliceAI: 0.09 (no splice impact)
- BayesDel: 0.285 (benign range)
- REVEL: 0.594 (intermediate
- not clearly benign). Predictions are not concordantly benign.
Sources
BP5 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. Details ▾Hide ▴
Evidence considered
- No alternate mechanism identified that would exclude this missense variant from pathogenicity.
BP6 No reputable source has reported NM_000135.3:c.2942G>C as benign. ClinVar classification is Uncertain significance, not benign. Details ▾Hide ▴
PS5 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). Details ▾Hide ▴
Evidence considered
- ClinVar VariationID 435127: Uncertain significance
- no pathogenic assertion from any submitter.
Sources
Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_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. Details ▾Hide ▴
Evidence considered
- Missense substitution
- variant bucket 'other'
- not eligible for generic PVS1.
Sources
pvs1_variant_assessmentpvs1_generic_framework ↗
PM3 N/ANot assessed for this case as specified in the skip list. Details ▾Hide ▴
No further detail was recorded.
PM4 N/ANot assessed for this case as specified in the skip list. Details ▾Hide ▴
No further detail was recorded.
PM5 N/AUnable 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. Details ▾Hide ▴
Evidence considered
- No same-residue ClinVar candidates with a different pathogenic missense change at codon 981.
Sources
pm5_candidates
BP3 N/ANM_000135.3:c.2942G>C is a single-nucleotide missense substitution, not an in-frame insertion or deletion. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ANM_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. Details ▾Hide ▴
Evidence considered
- Missense substitution
- BP7 is for synonymous variants only.
Identifiers
- Gene
- FANCA
- Transcript
- NM_000135.3
- Coding (HGVS c.)
- NM_000135.3:c.2942G>C
- Protein (HGVS p.)
- NP_000126.2:p.(Cys981Ser)
- GRCh38
- chr16:89758616 C>G
- GRCh37
- chr16:89825024 C>G
- ClinVar
- 435127
Gene diagram
Every interpreted variant in FANCA, mapped onto the exon structure of NM_000135.3. Select a row to find it on the plot.
FANCANM_000135.3
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in FANCA
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
Statements
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.594
- BayesDel
- 0.285
How the predictions were used
PP3 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. Details ▾Hide ▴
Evidence considered
- REVEL: 0.594 (intermediate/borderline)
- BayesDel: 0.285 (benign range)
- SpliceAI max delta: 0.09 (no splice impact).
Sources
BP4 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. Details ▾Hide ▴
Evidence considered
- SpliceAI: 0.09 (no splice impact)
- BayesDel: 0.285 (benign range)
- REVEL: 0.594 (intermediate
- not clearly benign). Predictions are not concordantly benign.
Sources
BP7 N/ANM_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. Details ▾Hide ▴
Evidence considered
- Missense substitution
- BP7 is for synonymous variants only.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.09). REVEL score = 0.594. BayesDel score = 0.285232.
6 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
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PMID 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.Richards S et al. · 2015ACMG/AMP standards and guidelines for the interpretation of sequence variants. This is a general classification framework paper and does not mention FANCA or NM_000135.3:c.2942G>C.Does not name this variant
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PMID 18197057 ↗Carrier screening in individuals of Ashkenazi Jewish descent.Gross SJ et al. · 2008ACMG practice guideline on carrier screening in individuals of Ashkenazi Jewish descent. Discusses founder mutations in genes associated with Jewish genetic disorders including Tay-Sachs, Canavan, cystic fibrosis, and familial dysautonomia. FANCA c.2942G>C is not mentioned.Does not name this variant
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PMID 19888064 ↗ACOG Committee Opinion No. 442: Preconception and prenatal carrier screening for genetic diseases in individuals of Eastern European Jewish descent.2009ACOG Committee Opinion on preconception and prenatal carrier screening for genetic diseases in individuals of Eastern European Jewish descent. Mentions Fanconi anemia group C as one of several disorders for which carrier screening is available. NM_000135.3:c.2942G>C is not mentioned.Does not name this variant
Quoted passage
Carrier screening is available for mucolipidosis IV, Niemann-Pick disease type A, Fanconi anemia group C, Bloom syndrome, and Gaucher disease.
Page 950-953; Table 1 lists Fanconi anemia group C with carrier frequency 1/89.
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PMID 26389210 ↗Genetics of Breast and Gynecologic Cancers (PDQ®): Health Professional Version.PDQ Cancer Genetics Editorial Board · 2002PDQ Cancer Genetics Editorial Board summary on Genetics of Breast and Gynecologic Cancers. General cancer genetics resource. NM_000135.3:c.2942G>C is not mentioned.Does not name this variant
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PMID 26389258 ↗Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Version.PDQ Cancer Genetics Editorial Board · 2002PDQ Cancer Genetics Editorial Board summary on Cancer Genetics Risk Assessment and Counseling. General cancer genetics resource. NM_000135.3:c.2942G>C is not mentioned.Does not name this variant
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PMID 26389333 ↗Genetics of Skin Cancer (PDQ®): Health Professional Version.PDQ Cancer Genetics Editorial Board · 2002PDQ Cancer Genetics Editorial Board summary on Genetics of Skin Cancer. General cancer genetics resource. NM_000135.3:c.2942G>C is not mentioned.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
SpliceAI Lookup
Recorded maximum delta 0.090
Open source ↗
ClinVar
2 Uncertain significance
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/435127/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/16-89825024-C-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr16-89758616-C-G?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/16-89758616-C-G
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000135.3%3Ac.2942…
- OncoKB ↗www.oncokb.org/gene/FANCA/C981S
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=FANCA+c.2942G%3EC
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
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
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.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.