About FANCD2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
FANCD2 c.266A>G, p.(Tyr89Cys)
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
PM2Moderate
PM2 · moderate
This variant is absent from gnomAD v2.1 and v4.1 population databases, meeting the PM2 threshold (<0.1% allele frequency) under generic ACMG/AMP 2015 criteria.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
Multiple lines of computational evidence suggest no significant impact on the gene product. REVEL score is 0.297 (below pathogenic threshold), BayesDel score is -0.03757 (negative, supporting a benign interpretation), and SpliceAI predicts no splicing alteration (max delta = 0.02).
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 moderate, BP4 supporting benign; combination = 1 moderate + 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
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.020 maximum delta
Recorded SpliceAI maximum delta score: 0.020. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
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. FANCD2, a tumor suppressor and DNA repair protein, is infrequently altered in cancer. Germline mutations of FANCD2 are associated with the cancer pred
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 · 5 not met · 15 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
PM2 is met at moderate strength: the variant is absent from gnomAD v2.1 and v4.1 population databases.
BP4 is met at supporting benign strength: REVEL (0.297), BayesDel (-0.03757), and SpliceAI (max delta 0.02) all predict a neutral or non-damaging effect.
PVS1 is not applicable because this is a missense substitution (p.Tyr89Cys), not a null variant per ClinGen PVS1 recommendations (PMC6185798).
PP3 is not met: the same in silico evidence that supports BP4 fails to support a pathogenic computational prediction.
The majority of criteria (PS1-PS4, PM1, PM6, PP1-PP2, PP4, BS2-BS4, BP2, BP5-BP6) cannot be assessed due to a complete absence of variant-specific data in ClinVar, gnomAD, the literature, and functional databases.
Under the generic ACMG/AMP 2015 combination rules (PMID:25741868), one moderate pathogenic criterion (PM2) and one supporting benign criterion (BP4) do not meet the threshold for likely pathogenic (requires ≥3 moderate or 1 strong + ≥1 moderate) or likely benign (requires ≥2 supporting benign or 1 strong benign + 1 supporting benign). The variant is classified as a Variant of Uncertain Significance (VUS).
No criteria match.
Met · 2
PM2 ModerateThis variant is absent from gnomAD v2.1 and v4.1 population databases, meeting the PM2 threshold (<0.1% allele frequency) under generic ACMG/AMP 2015 criteria. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (exomes) and gnomAD v4.1 (exomes/genomes). gnomAD-Canada also shows zero allele count.
Still missing
- gnomAD v2.1 and v4.1 returned null AC/AN values rather than explicit zero-counts with coverage
- confirmation of adequate sequencing coverage at this position is recommended. gnomAD-Canada reports AC=0
- AN=0 (no coverage).
Sources
BP4 SupportingMultiple lines of computational evidence suggest no significant impact on the gene product. REVEL score is 0.297 (below pathogenic threshold), BayesDel score is -0.03757 (negative, supporting a benign interpretation), and SpliceAI predicts no splicing alteration (max delta = 0.02). Details ▾Hide ▴
Evidence considered
- REVEL: 0.297
- BayesDel: -0.03757
- SpliceAI max delta: 0.02.
Still missing
- REVEL score 0.297 is in an intermediate range
- HCI Prior not available for FANCD2.
Sources
Not met · 5 · evaluated, threshold not reached
PP3 Multiple lines of computational evidence do not support a deleterious effect. REVEL score is 0.297 (below the 0.5 pathogenic threshold), BayesDel score is -0.03757 (negative, benign-leaning), and SpliceAI predicts no splicing impact (max delta = 0.02). Details ▾Hide ▴
Evidence considered
- REVEL: 0.297
- BayesDel: -0.03757
- SpliceAI max delta: 0.02.
Sources
PP5 No reputable source has recently reported this variant as pathogenic. The variant is absent from ClinVar and has not been classified by any expert panel or clinical laboratory. Details ▾Hide ▴
BA1 The variant is absent from gnomAD v2.1 and v4.1, and therefore does not meet the BA1 threshold (>1% allele frequency under generic ACMG/AMP). Details ▾Hide ▴
Evidence considered
- Variant absent from gnomAD
- allele frequency effectively zero.
Sources
BS1 The variant is absent from gnomAD v2.1 and v4.1, and therefore does not meet the BS1 threshold (>0.3% allele frequency under generic ACMG/AMP). Details ▾Hide ▴
Evidence considered
- Variant absent from gnomAD
- allele frequency effectively zero.
Sources
PS5 No reputable source has classified this variant as pathogenic or likely pathogenic. The variant is entirely absent from ClinVar. Details ▾Hide ▴
Not assessed · 15 · no assessment recorded
PS1 No pathogenic or likely pathogenic variant with the same amino acid change (p.Tyr89Cys) has been identified in ClinVar or the literature to serve as a PS1 comparator. Details ▾Hide ▴
Evidence considered
- ClinVar contains no entries for this variant or any other variant producing p.Tyr89Cys.
Still missing
- No comparator variant at residue 89 available for PS1 assessment.
Sources
PS2 No de novo observation with confirmed paternity and maternity has been reported for this variant. The variant is absent from ClinVar and the literature. Details ▾Hide ▴
Evidence considered
- No de novo reports in ClinVar or literature.
Still missing
- No family-based sequencing data available.
Sources
PS3 No well-established in vitro or in vivo functional studies have been identified for this variant. OncoKB reports no variant-specific reviewed functional evidence. Details ▾Hide ▴
Evidence considered
- OncoKB classification: Unknown Oncogenic Effect
- no variant-specific functional studies curated.
Still missing
- No functional assay data available for p.Tyr89Cys.
Sources
PS4 No case-control or prevalence data are available. The variant is absent from ClinVar and has not been reported in any affected cohorts. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no affected-vs-control comparisons available.
Still missing
- No case-control study or cohort data available.
Sources
PM1 Residue Y89 is not located within a statistically significant mutational hotspot (CancerHotspots: no signal). Domain-level critical functional region data are not available in the current evidence set. Details ▾Hide ▴
Evidence considered
- CancerHotspots: not significant
- OncoKB: no domain-level pathogenic enrichment reported for Y89.
Still missing
- FANCD2 domain architecture and critical functional domain mapping not assessed.
Sources
PM6 No assumed de novo observation (without confirmation of paternity and maternity) has been reported for this variant. Details ▾Hide ▴
Evidence considered
- No de novo reports in ClinVar or literature.
Still missing
- No de novo data available.
Sources
PP1 No cosegregation data are available for this variant. No family studies have been reported. Details ▾Hide ▴
Evidence considered
- No family-based segregation analysis available.
Still missing
- No cosegregation data.
PP2 HCI Prior score is not available for FANCD2 (gene not supported by the HCI predictor), precluding assessment of missense constraint (z-score). Details ▾Hide ▴
Evidence considered
- HCI Prior: gene FANCD2 not supported
- no missense constraint score available.
Still missing
- No missense constraint metric available for FANCD2 in current toolset.
PP4 No patient phenotype or family history data are available for this variant. The variant has not been reported in any clinical context. Details ▾Hide ▴
Evidence considered
- No clinical phenotype data available.
Still missing
- No proband phenotype or clinical history available.
BS2 No data are available regarding observation of this variant in healthy adults, particularly in a homozygous state or in trans with a known pathogenic variant. Details ▾Hide ▴
Evidence considered
- No healthy adult observation data available.
Still missing
- No data on variant presence in healthy adult cohorts.
BS3 No well-established functional studies demonstrating no damaging effect have been identified for this variant. Details ▾Hide ▴
Evidence considered
- OncoKB: no variant-specific functional evidence curated.
Still missing
- No functional assay data available for p.Tyr89Cys.
Sources
BS4 No segregation data in affected families are available to assess lack of cosegregation with disease. Details ▾Hide ▴
Evidence considered
- No family segregation data available.
Still missing
- No segregation analysis data.
BP2 No data are available regarding observation of this variant in trans with a pathogenic variant (relevant for this autosomal recessive disorder) or in cis with a pathogenic variant. Details ▾Hide ▴
Evidence considered
- No trans/cis configuration data available.
Still missing
- No phase or co-occurrence data with other FANCD2 variants.
BP5 No data are available regarding an alternative molecular basis for disease in a case carrying this variant. Details ▾Hide ▴
Evidence considered
- No alternative molecular diagnosis data available.
Still missing
- No data on alternative genetic findings in carriers.
BP6 No reputable source has reported this variant as benign or likely benign. The variant is absent from ClinVar. Details ▾Hide ▴
Evidence considered
- ClinVar: zero submissions
- no benign classification by any source.
Sources
Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 is not applicable to missense substitutions. This variant (c.266A>G, p.Tyr89Cys) does not fall into the null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants under the ClinGen PVS1 decision tree (PMC6185798). Details ▾Hide ▴
Evidence considered
- Missense substitution p.Tyr89Cys
- variant bucket classified as 'other' per PVS1 decision tree.
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PM5 N/ANo pathogenic or likely pathogenic missense variants have been identified at the same residue (Y89) in ClinVar. The automated PM5 candidate search returned zero same-residue comparators. Details ▾Hide ▴
Evidence considered
- PM5 candidate search: 0 same-residue candidates
- no P/LP variants at Y89 in ClinVar.
Sources
pm5_candidatesclinvar ↗
BP1 N/AFANCD2 is a known Fanconi anemia gene in which both truncating and missense variants are established causes of disease. BP1 (missense variant in a gene where only truncating variants cause disease) does not apply. Details ▾Hide ▴
Evidence considered
- FANCD2 loss-of-function mechanism supported
- missense variants are a recognized cause of Fanconi anemia (PMID:29376519).
Sources
pvs1_gene_context
BP3 N/AThis is a single-nucleotide substitution, not an in-frame deletion/insertion in a repetitive region. BP3 does not apply. Details ▾Hide ▴
Evidence considered
- Substitution variant
- no repeat region involvement.
BP7 N/ABP7 applies to synonymous (silent) variants with no predicted splice impact. This variant is a missense substitution (p.Tyr89Cys) and is not silent. Details ▾Hide ▴
Evidence considered
- Missense variant
- not synonymous.
Identifiers
- Gene
- FANCD2
- Transcript
- NM_033084.4
- Coding (HGVS c.)
- NM_033084.4:c.266A>G
- Protein (HGVS p.)
- NP_149075.2:p.(Tyr89Cys)
- GRCh38
- chr3:10034529 A>G
- GRCh37
- chr3:10076213 A>G
Gene diagram
Every interpreted variant in FANCD2, mapped onto the exon structure of NM_033084.4. Select a row to find it on the plot.
FANCD2NM_033084.4
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 FANCD2
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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 v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.297
- BayesDel
- -0.038
How the predictions were used
BP4 SupportingMultiple lines of computational evidence suggest no significant impact on the gene product. REVEL score is 0.297 (below pathogenic threshold), BayesDel score is -0.03757 (negative, supporting a benign interpretation), and SpliceAI predicts no splicing alteration (max delta = 0.02). Details ▾Hide ▴
Evidence considered
- REVEL: 0.297
- BayesDel: -0.03757
- SpliceAI max delta: 0.02.
Still missing
- REVEL score 0.297 is in an intermediate range
- HCI Prior not available for FANCD2.
Sources
PP3 Multiple lines of computational evidence do not support a deleterious effect. REVEL score is 0.297 (below the 0.5 pathogenic threshold), BayesDel score is -0.03757 (negative, benign-leaning), and SpliceAI predicts no splicing impact (max delta = 0.02). Details ▾Hide ▴
Evidence considered
- REVEL: 0.297
- BayesDel: -0.03757
- SpliceAI max delta: 0.02.
Sources
BP7 N/ABP7 applies to synonymous (silent) variants with no predicted splice impact. This variant is a missense substitution (p.Tyr89Cys) and is not silent. Details ▾Hide ▴
Evidence considered
- Missense variant
- not synonymous.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.297. BayesDel score = -0.03757.
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.020
Open source ↗
ClinVar
Captured ClinVar source record
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/?term=NM_033084.4%3Ac.266A%3EG
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/3-10076213-A-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr3-10034529-A-G?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/3-10034529-A-G
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_033084.4%3Ac.266A…
- OncoKB ↗www.oncokb.org/gene/FANCD2/Y89C
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=FANCD2+c.266A%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
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.297. BayesDel score = -0.03757.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. FANCD2, a tumor suppressor and DNA repair protein, is infrequently altered in cancer. Germline mutations of FANCD2 are associated with the cancer pred
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.