About FANCL
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
FANCL c.238C>G, p.(Leu80Val)
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 present at very low frequency in gnomAD (v2.1 overall AF=0.018%; v4.1 overall AF=0.015%), meeting the PM2 supporting threshold of <0.1% for non-VCEP assessment. However, caution is warranted: gnomAD v4.1 reports two homozygotes (including one in the Middle Eastern population), which is unexpected for an autosomal recessive severe pediatric disorder and raises the possibility that this variant may not be fully penetrant.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
Multiple lines of computational evidence suggest no impact on the gene product: REVEL score is 0.193 (benign range), BayesDel score is -0.271 (predicts benign), and SpliceAI predicts no splicing impact (max delta 0.04).
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
241 / 1,612,942 alleles
gnomAD v4.1: 241 / 1,612,942 alleles. Recorded AF 0.000149416. Recorded homozygote count 2.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000180677; MAF= 0.01807%, 51/282272 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.000818491; MAF= 0.08185%, 25/30544 alleles, homozygotes = 0); grpmax FAF= 0.00056865.
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
6 reported laboratory submissions
6 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.
27 criteria with recorded statuses: 2 met · 7 not met · 15 not assessed · 3 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_018062.3:c.238C>G (p.Leu80Val) in FANCL is a missense variant observed at very low frequency in gnomAD (overall AF 0.015–0.018%) but with two homozygotes in gnomAD v4.1, which is unexpected for a fully penetrant autosomal recessive Fanconi anemia gene.
Multiple computational tools predict a benign effect: REVEL score 0.193, BayesDel score -0.271, and SpliceAI max delta 0.04, providing supporting evidence against pathogenicity (BP4_Supporting).
No functional studies, segregation data, de novo reports, or case-control data are available for this variant. It has been reported in ClinVar as Uncertain significance by six clinical laboratories with no expert panel review.
No variant-specific evidence was identified in the literature. All ClinVar-associated publications are general guidelines (ACMG/AMP, Sherloc), carrier screening recommendations, GeneReviews, or PDQ cancer genetics summaries that do not mention or evaluate this specific variant.
Under generic ACMG/AMP 2015 criteria, the available evidence yields one supporting pathogenic criterion (PM2_Supporting) and one supporting benign criterion (BP4_Supporting), resulting in an Uncertain significance classification.
No criteria match.
Met · 2
PM2 SupportingThis variant is present at very low frequency in gnomAD (v2.1 overall AF=0.018%; v4.1 overall AF=0.015%), meeting the PM2 supporting threshold of <0.1% for non-VCEP assessment. However, caution is warranted: gnomAD v4.1 reports two homozygotes (including one in the Middle Eastern population), which is unexpected for an autosomal recessive severe pediatric disorder and raises the possibility that this variant may not be fully penetrant. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 51/282
- 272 alleles (AF=0.018%)
- 0 homozygotes
- grpmax FAF=0.000569 (SAS).
- gnomAD v4.1: 241/1
- 612
- 942 alleles (AF=0.015%)
- 2 homozygotes
- grpmax FAF=0.000897 (Middle Eastern).
Still missing
- Two homozygotes in gnomAD v4.1 are unexpected for a fully penetrant recessive Fanconi anemia gene
- clinical status of these individuals is unknown.
Sources
BP4 SupportingMultiple lines of computational evidence suggest no impact on the gene product: REVEL score is 0.193 (benign range), BayesDel score is -0.271 (predicts benign), and SpliceAI predicts no splicing impact (max delta 0.04). Details ▾Hide ▴
Evidence considered
- REVEL: 0.193 (below 0.5 pathogenic threshold
- in benign range).
- BayesDel: -0.271 (negative
- predicts benign).
- SpliceAI: max delta 0.04 (no predicted splicing alteration).
Sources
Not met · 7 · evaluated, threshold not reached
PS3 No well-established in vitro or in vivo functional studies have been performed specifically for NM_018062.3:c.238C>G (p.Leu80Val). OncoKB reports Unknown Oncogenic Effect with no variant-specific functional evidence. No variant-specific functional data were identified in the literature. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect
- no variant-specific functional studies identified.
Still missing
- No functional studies for this specific missense variant.
Sources
PM1 Residue Leu80 does not lie in a statistically significant mutational hotspot in FANCL (Hotspots: residue_significant=false). No evidence that codon 80 resides in a well-established critical functional domain devoid of benign missense variation. Details ▾Hide ▴
Evidence considered
- Hotspots: residue not significant
- exact variant not listed in hotspot database.
Still missing
- No domain-level constraint data showing absence of benign variation at this residue.
PP3 Multiple in silico predictors do not support a deleterious effect: REVEL score is 0.193 (below the 0.5 pathogenic threshold), BayesDel score is -0.271 (predicts benign), and SpliceAI delta score is 0.04 (no predicted splicing impact). HCI prior not available for FANCL. Details ▾Hide ▴
Evidence considered
- REVEL: 0.193 (benign range).
- BayesDel: -0.271 (predicts benign).
- SpliceAI: max delta 0.04 (no splicing impact).
Sources
PP5 No reputable source has classified this variant as pathogenic. ClinVar consensus across 6 clinical laboratory submissions is Uncertain significance. None of the ClinVar-associated PMIDs (GeneReviews, PDQ summaries, carrier screening guidelines, ACMG/Sherloc method papers) provide a variant-specific pathogenic classification. Details ▾Hide ▴
Evidence considered
- ClinVar: 6 clinical labs report Uncertain significance
- no expert panel or reputable source classifies as pathogenic.
Sources
BA1 Allele frequency in all gnomAD populations is well below 1%. Highest subpopulation frequency is 0.165% (Middle Eastern, gnomAD v4.1). Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 max subpopulation AF: 0.082% (SAS).
- gnomAD v4.1 max subpopulation AF: 0.165% (Middle Eastern).
Sources
BS1 Allele frequency does not exceed 0.3% in any gnomAD population. Highest subpopulation frequency is 0.165% (Middle Eastern, gnomAD v4.1). Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 max subpopulation AF: 0.082% (SAS).
- gnomAD v4.1 max subpopulation AF: 0.165% (Middle Eastern).
Sources
BP6 No reputable source has classified this variant as benign. ClinVar consensus across 6 clinical laboratory submissions is Uncertain significance. Details ▾Hide ▴
Evidence considered
- ClinVar: 6 clinical labs report Uncertain significance
- no source classifies as benign.
Sources
Not assessed · 15 · no assessment recorded
PS1 No alternative nucleotide change at c.238 resulting in the same amino acid change (p.Leu80Val) was identified in ClinVar or the literature. No comparator variant available for PS1 assessment. Details ▾Hide ▴
Still missing
- No same-amino-acid alternative nucleotide changes identified at this codon.
PS2 No de novo reports with confirmed maternity and paternity were identified for this variant in ClinVar or the literature. Details ▾Hide ▴
Still missing
- No de novo observations reported.
PS4 No case-control study data or statistically significant enrichment in affected individuals is available for this variant. The variant has been observed in clinical testing (6 ClinVar laboratories report Uncertain significance) but without case counts or phenotype-stratified prevalence data. Details ▾Hide ▴
Evidence considered
- ClinVar: 6 clinical laboratory submissions
- all Uncertain significance.
Still missing
- No case-control comparison or affected-vs-control enrichment data.
Sources
PM5 No same-residue comparator missense variants were identified at codon 80 of FANCL in ClinVar. Classic PM5 (different missense change at the same residue, with the comparator established as pathogenic) cannot be applied. Details ▾Hide ▴
Evidence considered
- No same-residue pathogenic missense variants identified in ClinVar at codon 80.
Still missing
- No comparator missense changes at residue Leu80 available.
Sources
pm5_candidates
PM6 No de novo observations (with or without confirmed parentage) were identified for this variant in ClinVar or the literature. Details ▾Hide ▴
Still missing
- No de novo reports available.
PP1 No cosegregation data in affected family members is available for this variant. Details ▾Hide ▴
Still missing
- No segregation studies reported.
PP2 PP2 requires a gene with a low rate of benign missense variation where missense is a common disease mechanism. FANCL constraint metrics (e.g., gnomAD missense Z-score) were not available, and the presence of missense variants at appreciable frequency in population databases (including homozygotes) does not clearly support a low benign missense rate. Details ▾Hide ▴
Evidence considered
- No FANCL missense constraint metrics available.
Still missing
- No gene-level missense constraint data (e.g.
- Z-score
- LOEUF) available.
Sources
PP4 No patient phenotype or family history data are available to assess whether the clinical presentation is highly specific for Fanconi anemia with a single genetic etiology. Details ▾Hide ▴
Still missing
- No patient phenotype data available.
BS2 While gnomAD v4.1 reports 2 homozygotes for this variant, the clinical status of these individuals is unknown. Without confirmation that these are healthy adults, BS2 (observed in a healthy adult for a fully penetrant early-onset disorder) cannot be applied. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: 2 homozygotes
- but clinical phenotype unknown.
Still missing
- Clinical phenotype of homozygous individuals in gnomAD is unknown.
Sources
BS3 No well-established functional studies demonstrating no damaging effect have been performed for this specific variant. OncoKB reports Unknown Oncogenic Effect with no variant-specific data. Details ▾Hide ▴
Evidence considered
- No variant-specific functional studies available.
Still missing
- No functional studies for this variant.
Sources
BS4 No segregation data are available to assess lack of cosegregation with disease in affected family members. Details ▾Hide ▴
Still missing
- No segregation studies reported.
BP1 BP1 requires a gene where only truncating variants cause disease. FANCL has both missense and truncating variants reported in association with Fanconi anemia. Insufficient gene-level evidence to establish that missense variants in FANCL are not pathogenic. Details ▾Hide ▴
Evidence considered
- FANCL disease mechanism includes both truncating and missense variants.
Still missing
- Insufficient data on FANCL missense vs truncating variant disease spectrum.
Sources
pvs1_gene_context
BP2 No phasing data are available to determine whether this variant has been observed in trans with a pathogenic FANCL variant or in cis with a pathogenic variant in any individual. Details ▾Hide ▴
Still missing
- No phasing or allelic data available.
BP5 No data are available indicating this variant was found in a case with an alternative molecular basis for disease. Details ▾Hide ▴
Still missing
- No alternative molecular basis data available.
PS5 PS5 requires a variant reported in affected individuals but without the statistical strength for PS4. No detailed case-level data describing affected individuals harboring this variant were available for independent evaluation. Details ▾Hide ▴
Evidence considered
- ClinVar submissions suggest clinical observation but lack case-level detail.
Still missing
- No case-level phenotype or count data available for review.
Sources
Not applicable · 3· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant (p.Leu80Val) and does not fall into the null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants required for generic PVS1 application per ClinGen SVI PVS1 recommendations (PMC6185798). Details ▾Hide ▴
Evidence considered
- Missense substitution
- variant bucket 'other'
- not eligible for generic PVS1 framework.
Sources
BP3 N/ABP3 applies to in-frame deletions/insertions in repetitive regions; not applicable to a missense substitution. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ABP7 applies to silent (synonymous) variants with no predicted splice impact. This is a missense variant (c.238C>G, p.Leu80Val) and does not qualify. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- FANCL
- Transcript
- NM_018062.3
- Coding (HGVS c.)
- NM_018062.3:c.238C>G
- Protein (HGVS p.)
- NP_060532.2:p.(Leu80Val)
- GRCh38
- chr2:58226763 G>C
- GRCh37
- chr2:58453898 G>C
- ClinVar
- 408230
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
241 / 1,612,942 alleles
AF 0.000149 · 2 homozygotes · FAF 0.000897
gnomAD v2.1
51 / 282,272 alleles
AF 0.000181 · 0 homozygotes · FAF 0.000569
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 0.00015 · 241 / 1,612,942 alleles · 2 hom · FAF 0.0009
| Middle Eastern10 / 6,046 | 0.00171 hom |
| South Asian71 / 90,974 | 0.000781 hom |
| Remaining individuals11 / 62,466 | 0.00018 |
| Admixed American9 / 59,944 | 0.00015 |
| European (non-Finnish)140 / 1,179,544 | 0.00012 |
0 alternate alleles recorded in 5 other groups: European (Finnish), Amish, East Asian, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 0.00018 · 51 / 282,272 alleles · 0 hom · FAF 0.00057
| South Asian25 / 30,544 | 0.00082 |
| Remaining individuals2 / 7,200 | 0.00028 |
| European (non-Finnish)20 / 128,888 | 0.00016 |
| Admixed American4 / 35,376 | 0.00011 |
0 alternate alleles recorded in 4 other groups: African/African American, Ashkenazi Jewish, East Asian, European (Finnish).
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0.000149416; MAF= 0.01494%, 241/1612942 alleles, homozygotes = 2) and has highest observed frequency in the Middle Eastern population (AF= 0.00165399; MAF= 0.16540%, 10/6046 alleles, homozygotes = 1); grpmax FAF= 0.00089698.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000180677; MAF= 0.01807%, 51/282272 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.000818491; MAF= 0.08185%, 25/30544 alleles, homozygotes = 0); grpmax FAF= 0.00056865.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.193
- BayesDel
- -0.271
How the predictions were used
BP4 SupportingMultiple lines of computational evidence suggest no impact on the gene product: REVEL score is 0.193 (benign range), BayesDel score is -0.271 (predicts benign), and SpliceAI predicts no splicing impact (max delta 0.04). Details ▾Hide ▴
Evidence considered
- REVEL: 0.193 (below 0.5 pathogenic threshold
- in benign range).
- BayesDel: -0.271 (negative
- predicts benign).
- SpliceAI: max delta 0.04 (no predicted splicing alteration).
Sources
PP3 Multiple in silico predictors do not support a deleterious effect: REVEL score is 0.193 (below the 0.5 pathogenic threshold), BayesDel score is -0.271 (predicts benign), and SpliceAI delta score is 0.04 (no predicted splicing impact). HCI prior not available for FANCL. Details ▾Hide ▴
Evidence considered
- REVEL: 0.193 (benign range).
- BayesDel: -0.271 (predicts benign).
- SpliceAI: max delta 0.04 (no splicing impact).
Sources
BP7 N/ABP7 applies to silent (synonymous) variants with no predicted splice impact. This is a missense variant (c.238C>G, p.Leu80Val) and does not qualify. Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04). REVEL score = 0.193. BayesDel score = -0.271414.
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
-
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 joint consensus guideline establishing the framework for sequence variant interpretation. This methodological paper does not discuss FANCL or NM_018062.3:c.238C>G.Does not name this variant
-
PMID 18197057 ↗Carrier screening in individuals of Ashkenazi Jewish descent.Gross SJ et al. · 2008ACMG practice guideline on carrier screening for Ashkenazi Jewish genetic disorders. Discusses screening panels for Tay-Sachs, cystic fibrosis, familial dysautonomia, and other conditions prevalent in the Ashkenazi population. Does not mention FANCL or NM_018062.3:c.238C>G.Does not name this variant
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PMID 20301575 ↗Fanconi Anemia.Adam MP et al. · 1993GeneReviews entry on Fanconi Anemia, providing a general overview of the disorder including its genetic causes, clinical features, diagnosis, and management. Does not specifically evaluate or classify NM_018062.3:c.238C>G.Does not name this variant
-
PMID 26389210 ↗Genetics of Breast and Gynecologic Cancers (PDQ®): Health Professional Version.PDQ Cancer Genetics Editorial Board · 2002PDQ Cancer Genetics summary on Genetics of Breast and Gynecologic Cancers. General overview of hereditary breast/gynecologic cancer genes. Does not evaluate FANCL or NM_018062.3:c.238C>G.Does not name this variant
-
PMID 26389258 ↗Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Version.PDQ Cancer Genetics Editorial Board · 2002PDQ Cancer Genetics summary on Cancer Genetics Risk Assessment and Counseling. General overview of cancer risk assessment and genetic counseling principles. Does not evaluate FANCL or NM_018062.3:c.238C>G.Does not name this variant
-
PMID 26389333 ↗Genetics of Skin Cancer (PDQ®): Health Professional Version.PDQ Cancer Genetics Editorial Board · 2002PDQ Cancer Genetics summary on Genetics of Skin Cancer. This is a general overview of hereditary skin cancer syndromes and their genetic underpinnings. Does not evaluate FANCL or NM_018062.3:c.238C>G.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
241 / 1,612,942 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
6 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/408230/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/2-58453898-G-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr2-58226763-G-C?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/2-58226763-G-C
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_018062.3%3Ac.238C…
- OncoKB ↗www.oncokb.org/gene/FANCL/L80V
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=FANCL+c.238C%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= 0.000149416; MAF= 0.01494%, 241/1612942 alleles, homozygotes = 2) and has highest observed frequency in the Middle Eastern population (AF= 0.00165399; MAF= 0.16540%, 10/6046 alleles, homozygotes = 1); grpmax FAF= 0.00089698.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000180677; MAF= 0.01807%, 51/282272 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.000818491; MAF= 0.08185%, 25/30544 alleles, homozygotes = 0); grpmax FAF= 0.00056865.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (6 clinical laboratories). (ClinVarID = 408230)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04). REVEL score = 0.193. BayesDel score = -0.271414.
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.