About FANCL
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
FANCL c.233C>G, p.(Pro78Arg)
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: 1
Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1 and present at extremely low frequency in gnomAD v4.1 (global AF=0.000496%, 8/1,612,860 alleles, no homozygotes; grpmax FAF=1.065e-05), meeting the PM2 threshold of <0.1% for a rare variant.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
Multiple lines of computational evidence suggest no impact on the gene product: REVEL score 0.105, BayesDel score -0.364706, and SpliceAI max delta score 0.04 (no predicted splicing impact).
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: PM2 supporting, BP4 supporting benign; combination = 1 supporting + 1 supporting benign, 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.
gnomAD v4.1
gnomAD v2.1
Population frequency
8 / 1,612,860 alleles
gnomAD v4.1: 8 / 1,612,860 alleles. Recorded AF 4.96013e-06. Recorded homozygote count 0.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
SpliceAI score
0.040 maximum delta
Recorded SpliceAI maximum delta score: 0.040. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
2 reported laboratory submissions
2 Uncertain significance.
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. FANCL, an E3 ubiquitin ligase involved in DNA repair, is infrequently altered in cancer. Germline mutations of FANCL are associated with the cancer pr
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.
26 criteria with recorded statuses: 2 met · 8 not met · 12 not assessed · 4 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
This missense variant (c.233C>G, p.Pro78Arg) in FANCL is absent from gnomAD v2.1 and present at extremely low frequency in gnomAD v4.1 (AF=0.000496%, 8/1,612,860 alleles, no homozygotes), meeting PM2 at supporting strength.
Multiple lines of computational evidence (REVEL 0.105, BayesDel -0.364706, SpliceAI max delta 0.04) suggest no damaging impact on the gene product, meeting BP4 at supporting benign strength.
This variant has been reported in ClinVar as Uncertain significance by two clinical laboratories with no expert panel classification; no case-control, functional, or segregation data specific to this variant were identified.
With one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4), the evidence is balanced and the variant is classified as Uncertain significance per ACMG/AMP 2015 combination rules (PMID:25741868).
No criteria match.
Met · 2
PM2 SupportingThis variant is absent from gnomAD v2.1 and present at extremely low frequency in gnomAD v4.1 (global AF=0.000496%, 8/1,612,860 alleles, no homozygotes; grpmax FAF=1.065e-05), meeting the PM2 threshold of <0.1% for a rare variant. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1.
- gnomAD v4.1: AF=4.96e-06 (8/1
- 612
- 860 alleles
- 0 homozygotes)
- grpmax FAF=1.065e-05.
Sources
BP4 SupportingMultiple lines of computational evidence suggest no impact on the gene product: REVEL score 0.105, BayesDel score -0.364706, and SpliceAI max delta score 0.04 (no predicted splicing impact). Details ▾Hide ▴
Evidence considered
- REVEL: 0.105 (supports benign).
- BayesDel: -0.364706 (supports benign).
- SpliceAI: max delta 0.04 (no splicing impact).
Sources
Not met · 8 · evaluated, threshold not reached
PS3 No variant-specific functional studies were identified. OncoKB reports Unknown Oncogenic Effect for this variant. In silico predictors REVEL (0.105) and BayesDel (-0.364706) do not support a damaging functional effect. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect
- no variant-specific curated functional evidence.
- REVEL score 0.105 does not support a damaging effect.
- BayesDel score -0.364706 does not support a damaging effect.
Still missing
- No published functional studies specific to this variant.
Sources
PS4 No case-control studies demonstrating significantly increased prevalence of this variant in affected individuals compared to controls were identified. The variant is reported in ClinVar only as Uncertain significance by two clinical laboratories. Details ▾Hide ▴
Evidence considered
- ClinVar: Uncertain significance
- 2 clinical laboratories
- single submitter review status.
Still missing
- No case-control or cohort data for this variant.
Sources
PM1 This variant does not lie in a statistically significant mutational hotspot. Residue Pro78 is not in a well-characterized functional domain with enrichment of pathogenic missense variants in FANCL. Details ▾Hide ▴
Evidence considered
- Cancer Hotspots: residue not significant
- exact variant not listed.
PP3 Multiple in silico tools predict a benign effect: REVEL score 0.105 (below the commonly used 0.5 threshold), BayesDel score -0.364706 (negative score supports benign), and SpliceAI max delta score 0.04 (no predicted splicing impact). Details ▾Hide ▴
Evidence considered
- REVEL: 0.105 (does not support pathogenicity).
- BayesDel: -0.364706 (supports benign effect).
- SpliceAI max delta: 0.04 (no predicted splicing impact).
Sources
PP5 This variant is classified as Uncertain significance in ClinVar by two clinical laboratories (review status: criteria provided, single submitter). No reputable source has classified this variant as pathogenic. Details ▾Hide ▴
Evidence considered
- ClinVar: Uncertain significance (2 clinical laboratories). No expert panel classification as pathogenic.
Sources
BA1 This variant has a global allele frequency of 0.000496% in gnomAD v4.1 (grpmax FAF=1.065e-05), well below the BA1 threshold of >1%. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: global AF=4.96e-06 (0.000496%)
- far below 1% BA1 threshold.
Sources
BS1 This variant has a global allele frequency of 0.000496% in gnomAD v4.1 (grpmax FAF=1.065e-05), below the BS1 threshold of >0.3% for a disorder of this prevalence. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: global AF=4.96e-06 (0.000496%)
- below 0.3% BS1 threshold.
Sources
BP6 This variant is classified as Uncertain significance in ClinVar by two clinical laboratories; no reputable source has classified this variant as benign. Details ▾Hide ▴
Evidence considered
- ClinVar: Uncertain significance (not benign)
- 2 clinical laboratories.
Sources
Not assessed · 12 · no assessment recorded
PS1 No data available on other missense variants at the same amino acid position (Pro78) with an established pathogenic classification. Details ▾Hide ▴
Still missing
- No same-residue comparator variants identified for PS1 evaluation.
PS2 No de novo occurrence data available for this variant. Details ▾Hide ▴
Still missing
- No de novo testing or family study data available.
PM6 No de novo occurrence data available for this variant. Details ▾Hide ▴
Still missing
- No trio or de novo testing data available.
PP1 No cosegregation data available for this variant. Details ▾Hide ▴
Still missing
- No family segregation studies available.
PP2 HCI prior data are not available for FANCL; unable to assess the rate of benign missense variation in this gene relative to disease-causing missense variants. Details ▾Hide ▴
Evidence considered
- HCI prior: gene not supported in the HCI dataset.
Still missing
- No gene-specific missense constraint metric available.
PP4 No patient phenotype or family history data available for assessment. Details ▾Hide ▴
Still missing
- No patient-specific clinical data provided.
BS2 No data on observation of this variant in healthy adults beyond population database representation. Details ▾Hide ▴
Still missing
- No specific healthy adult cohort data for this variant.
BS3 No variant-specific functional studies demonstrating no damaging effect on protein function or splicing were identified. Details ▾Hide ▴
Still missing
- No functional assays of this variant available.
BS4 No nonsegregation data available for this variant. Details ▾Hide ▴
Still missing
- No family segregation or nonsegregation data available.
BP2 No data on this variant observed in trans with a pathogenic variant in FANCL, which would be expected for a recessive disorder. Details ▾Hide ▴
Still missing
- No phase data with other FANCL variants.
BP5 No data on this variant observed in a case with an alternate molecular basis for disease. Details ▾Hide ▴
Still missing
- No data on co-occurring explanatory variants.
PS5 No data on this variant observed in trans with a known pathogenic variant. Details ▾Hide ▴
Still missing
- No data on phase with other pathogenic FANCL variants.
Not applicable · 4· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis missense variant (c.233C>G, p.Pro78Arg) does not fall into the default generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants per ClinGen SVI PVS1 recommendations (PMC6185798). Details ▾Hide ▴
Evidence considered
- Variant is a missense substitution
- not a predicted null variant.
Sources
pvs1_variant_assessmentpvs1_generic_framework ↗
PM5 N/AUnable to confirm classic same-residue PM5 semantics; no pathogenic missense variants identified at the same amino acid residue (Pro78) for comparison. Details ▾Hide ▴
Evidence considered
- PM5 candidate search found no same-residue pathogenic comparator variants.
Sources
pm5_candidates
BP1 N/AFANCL is associated with Fanconi anemia, where both missense and loss-of-function variants are established disease mechanisms. BP1 applies only to genes where primarily truncating variants cause disease. Details ▾Hide ▴
Evidence considered
- FANCL loss-of-function mechanism is supported
- but missense variants are also a known disease mechanism in Fanconi anemia genes.
Sources
pvs1_gene_context
BP7 N/ABP7 applies to synonymous variants with no predicted splicing impact. This is a missense variant (c.233C>G, p.Pro78Arg) and does not qualify. Details ▾Hide ▴
Evidence considered
- Variant is missense (p.Pro78Arg)
- not synonymous.
Identifiers
- Gene
- FANCL
- Transcript
- NM_018062.3
- Coding (HGVS c.)
- NM_018062.3:c.233C>G
- Protein (HGVS p.)
- NP_060532.2:p.(Pro78Arg)
- GRCh38
- chr2:58226768 G>C
- GRCh37
- chr2:58453903 G>C
- ClinVar
- 2199165
Gene diagram
Every interpreted variant in FANCL, mapped onto the exon structure of NM_018062.3. Select a row to find it on the plot.
FANCLNM_018062.3
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 FANCL
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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
8 / 1,612,860 alleles
AF 4.96e-06 · 0 homozygotes · FAF 1.06e-05
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 5e-06 · 8 / 1,612,860 alleles · 0 hom · FAF 1.1e-05
| Middle Eastern1 / 6,072 | 0.00016 |
| Remaining individuals3 / 62,454 | 4.8e-05 |
| African/African American3 / 74,796 | 4e-05 |
| European (non-Finnish)1 / 1,179,488 | 8.5e-07 |
0 alternate alleles recorded in 6 other groups: Admixed American, European (Finnish), Amish, East Asian, South Asian, Ashkenazi Jewish.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 4.96013e-06; MAF= 0.00050%, 8/1612860 alleles, homozygotes = 0) and has highest observed frequency in the Middle Eastern population (AF= 0.00016469; MAF= 0.01647%, 1/6072 alleles, homozygotes = 0); grpmax FAF= 1.065e-05.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.105
- BayesDel
- -0.365
How the predictions were used
BP4 SupportingMultiple lines of computational evidence suggest no impact on the gene product: REVEL score 0.105, BayesDel score -0.364706, and SpliceAI max delta score 0.04 (no predicted splicing impact). Details ▾Hide ▴
Evidence considered
- REVEL: 0.105 (supports benign).
- BayesDel: -0.364706 (supports benign).
- SpliceAI: max delta 0.04 (no splicing impact).
Sources
PP3 Multiple in silico tools predict a benign effect: REVEL score 0.105 (below the commonly used 0.5 threshold), BayesDel score -0.364706 (negative score supports benign), and SpliceAI max delta score 0.04 (no predicted splicing impact). Details ▾Hide ▴
Evidence considered
- REVEL: 0.105 (does not support pathogenicity).
- BayesDel: -0.364706 (supports benign effect).
- SpliceAI max delta: 0.04 (no predicted splicing impact).
Sources
BP7 N/ABP7 applies to synonymous variants with no predicted splicing impact. This is a missense variant (c.233C>G, p.Pro78Arg) and does not qualify. Details ▾Hide ▴
Evidence considered
- Variant is missense (p.Pro78Arg)
- not synonymous.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04). REVEL score = 0.105. BayesDel score = -0.364706.
5 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
-
PMID 18197057 ↗Carrier screening in individuals of Ashkenazi Jewish descent.Gross SJ et al. · 2008This guideline addresses carrier screening recommendations for individuals of Ashkenazi Jewish descent and does not discuss FANCL or any specific FANCL variants.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. Does not discuss FANCL or the c.233C>G variant.Does not name this variant
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PMID 20301575 ↗Fanconi Anemia.Adam MP et al. · 1993GeneReviews entry on Fanconi Anemia providing general clinical and genetic overview. Does not mention the specific variant c.233C>G (p.Pro78Arg).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 risk assessment and counseling summary. Provides general cancer genetics guidance and does not mention FANCL or the c.233C>G variant.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 genetics of skin cancer summary. General cancer genetics review that does not discuss FANCL or the c.233C>G variant.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
8 / 1,612,860 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.040
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/2199165/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/2-58453903-G-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr2-58226768-G-C?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/2-58226768-G-C
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_018062.3%3Ac.233C…
- OncoKB ↗www.oncokb.org/gene/FANCL/P78R
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=FANCL+c.233C%3EG
- 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 v4.1
This variant is present in gnomAD v4.1 (AF= 4.96013e-06; MAF= 0.00050%, 8/1612860 alleles, homozygotes = 0) and has highest observed frequency in the Middle Eastern population (AF= 0.00016469; MAF= 0.01647%, 1/6072 alleles, homozygotes = 0); grpmax FAF= 1.065e-05.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories). (ClinVarID = 2199165)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04). REVEL score = 0.105. BayesDel score = -0.364706.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. FANCL, an E3 ubiquitin ligase involved in DNA repair, is infrequently altered in cancer. Germline mutations of FANCL are associated with the cancer pr
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.