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FANCD2c.70A>GUncertain significance
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Variant interpretation report

FANCD2 c.70A>G, p.(Arg24Gly)

NM_033084.4:c.70A>G NP_149075.2:p.(Arg24Gly) View identifiers
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.

About FANCD2

No gene-level summary was recorded for this case.

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

The variant is extremely rare in population databases: absent from gnomAD v2.1 and gnomAD-Canada, and present at very low frequency in gnomAD v4.1 (AF 3.1e-06, 5/1,612,676 alleles, 0 homozygotes; grpmax FAF 1.24e-06), well below the PM2 threshold of <0.1%. Downgraded to supporting due to confirmed observations of 5 alleles.

Benign criteria applied · 1
BP4Supporting
BP4 · supporting

Multiple lines of computational evidence support a benign interpretation: REVEL score 0.023 (strongly benign), BayesDel score -0.631 (benign), and SpliceAI max delta 0.08 (no splicing impact). All in silico predictors are concordant for no impact on gene product.

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.

SpliceAI score
0.080 maximum delta

Recorded SpliceAI maximum delta score: 0.080. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4 → SpliceAI ↗
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
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

29 criteria with recorded statuses: 2 met · 6 not met · 14 not assessed · 7 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

NM_033084.4:c.70A>G (p.Arg24Gly) is a missense variant in exon 3 of FANCD2.

The variant is extremely rare in population databases (gnomAD v4.1 AF 3.1e-06, 5/1,612,676 alleles, 0 homozygotes; absent from gnomAD v2.1 and gnomAD-Canada), meeting PM2 at supporting level.

Multiple lines of computational evidence (REVEL 0.023, BayesDel -0.631, SpliceAI max delta 0.08) are concordant for a benign interpretation, meeting BP4 at supporting benign level.

The variant has been reported in ClinVar (VariationID 1692057) by a single submitter (Sema4) as uncertain significance; no reputable source has classified it as pathogenic or benign.

No functional studies, segregation data, de novo observations, case-control data, or variant-specific literature evidence were identified for this variant.

Five ClinVar-associated PMIDs were reviewed; none contained variant-specific evidence for NM_033084.4:c.70A>G.

With one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4) in conflict, and no additional criteria met, the variant is classified as Uncertain Significance (VUS) per generic ACMG/AMP 2015 combination rules.

Met · 2

PM2 SupportingThe variant is extremely rare in population databases: absent from gnomAD v2.1 and gnomAD-Canada, and present at very low frequency in gnomAD v4.1 (AF 3.1e-06, 5/1,612,676 alleles, 0 homozygotes; grpmax FAF 1.24e-06), well below the PM2 threshold of <0.1%. Downgraded to supporting due to confirmed observations of 5 alleles. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1: absent. gnomAD v4.1: AF 3.1e-06 (5/1
  • 612
  • 676 alleles
  • 0 homozygotes)
  • far below the 0.1% PM2 threshold. gnomAD-Canada: absent.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BP4 SupportingMultiple lines of computational evidence support a benign interpretation: REVEL score 0.023 (strongly benign), BayesDel score -0.631 (benign), and SpliceAI max delta 0.08 (no splicing impact). All in silico predictors are concordant for no impact on gene product. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.023 (strongly benign). BayesDel: -0.631 (benign). SpliceAI: max delta 0.08 (no splicing impact). All predictors concordant for benign interpretation.
Sources
revelbayesdelspliceai ↗

Not met · 6 · evaluated, threshold not reached

PP3 Multiple lines of computational evidence do not support a deleterious effect: REVEL score 0.023 (strongly benign), BayesDel score -0.631 (benign), and SpliceAI max delta 0.08 (no splicing impact). All in silico predictors are concordant for a benign interpretation. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.023 (strongly benign). BayesDel: -0.631 (benign). SpliceAI: max delta 0.08 (no splicing impact). All predictors concordant for benign.
Sources
revelbayesdelspliceai ↗
PP5 No reputable source has classified this variant as pathogenic. The sole ClinVar submission (Sema4) classifies as uncertain significance. The associated ClinVar PMIDs (GeneReviews, PDQ summaries, carrier screening guidelines) are general references that do not provide variant-specific pathogenic assertions. Details ▾Hide ▴
Evidence considered
  • ClinVar: single submitter (Sema4)
  • uncertain significance. Associated PMIDs are general reference articles that do not assert pathogenicity for this variant.
Sources
clinvar ↗PMID:20301575 ↗PMID:18197057 ↗PMID:26389210 ↗PMID:26389258 ↗PMID:26389333 ↗
BA1 The variant allele frequency in gnomAD v4.1 is 3.1e-06 (0.00031%), far below the BA1 threshold of >1%. BA1 is not met. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 AF: 3.1e-06 (0.00031%)
  • well below BA1 threshold of 1%.
Sources
gnomad_v4 ↗
BS1 The variant allele frequency in gnomAD v4.1 is 3.1e-06 (0.00031%), below the BS1 threshold of >0.3% for recessive disorders. BS1 is not met. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 AF: 3.1e-06 (0.00031%)
  • below BS1 threshold of 0.3%.
Sources
gnomad_v4 ↗
BP6 No reputable source classifies this variant as benign. The sole ClinVar submission (Sema4) classifies as uncertain significance. BP6 is not met. Details ▾Hide ▴
Evidence considered
  • ClinVar SCV002529537: Sema4 classifies as 'Uncertain significance'. No benign assertion from any reputable source.
Sources
clinvar ↗
PS5 No reputable source has classified this variant as pathogenic. The sole ClinVar submission (Sema4) classifies the variant as uncertain significance. Details ▾Hide ▴
Evidence considered
  • ClinVar SCV002529537: Sema4 classifies as 'Uncertain significance' (criteria provided
  • single submitter). No pathogenic assertion from any reputable source.
Sources
clinvar ↗

Not assessed · 14 · no assessment recorded

PS1 No known pathogenic variant with a different nucleotide change at the same codon (Arg24) was identified to serve as a PS1 comparator. Details ▾Hide ▴
Evidence considered
  • No comparator variant found at c.70 or codon Arg24 with established pathogenicity.
Still missing
  • No same-nucleotide pathogenic comparator available.
PS2 No de novo observation data (with both maternity and paternity confirmed) is available for this variant. Details ▾Hide ▴
Evidence considered
  • No de novo reports identified in ClinVar
  • literature
  • or other databases.
Still missing
  • No de novo data available.
PS3 No well-established in vitro or in vivo functional studies supporting a damaging effect on the gene product were identified for this variant. OncoKB reports unknown oncogenic effect with no variant-specific functional evidence. Details ▾Hide ▴
Evidence considered
  • OncoKB classification: Unknown Oncogenic Effect
  • no variant-specific functional studies found.
Still missing
  • No functional studies available for this variant.
Sources
oncokb ↗
PS4 No case-control or enriched case prevalence data are available. The variant is extremely rare in population databases, but no affected vs. unaffected comparison data exist. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1: 5/1
  • 612
  • 676 alleles (AF 3.1e-06)
  • ClinVar: single submitter
  • no enriched case observations.
Still missing
  • No case-control or case-enrichment data.
Sources
gnomad_v4 ↗clinvar ↗
PM1 Residue Arg24 is not located in a statistically significant mutational hotspot (hotspots screen negative), and no evidence establishes this as a critical well-established functional domain. Details ▾Hide ▴
Evidence considered
  • Hotspots analysis: residue not significant
  • exact variant not listed. No domain-specific functional criticality data.
Still missing
  • No hotspot or critical domain evidence for Arg24.
PM6 No de novo observation data (without confirmation of paternity and maternity) is available for this variant. Details ▾Hide ▴
Evidence considered
  • No de novo reports identified.
Still missing
  • No de novo data.
PP1 No cosegregation data with disease in affected family members is available. Details ▾Hide ▴
Evidence considered
  • No segregation analysis data available.
Still missing
  • No family segregation data.
PP2 Insufficient gene-level data to assess whether FANCD2 has a low rate of benign missense variation and whether missense variants are a common mechanism of disease, in the absence of VCEP-specific guidance. Details ▾Hide ▴
Evidence considered
  • No VCEP/CSPEC guidance for FANCD2 PP2 assessment
  • insufficient data for generic PP2 application.
Still missing
  • No gene-level missense constraint data in VCEP context.
PP4 No patient phenotype or family history data specific to FANCD2-related disease are available for assessment. Details ▾Hide ▴
Evidence considered
  • No patient phenotype data available.
Still missing
  • No phenotype or family history data.
BS2 No data are available on observation of this variant in healthy adult individuals with full penetrance expectation for Fanconi anemia. Details ▾Hide ▴
Evidence considered
  • gnomAD observations (5 alleles) lack phenotype data confirming healthy adult status in the context of a fully penetrant recessive disorder.
Still missing
  • No healthy adult observation data with phenotype confirmation.
BS3 No well-established in vitro or in vivo functional studies demonstrating no damaging effect on the gene product were identified for this variant. Details ▾Hide ▴
Evidence considered
  • No functional studies available demonstrating benign effect.
Still missing
  • No functional data demonstrating no damaging effect.
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 data.
BP2 No data on observation of this variant in trans with a known dominant pathogenic variant are available. Details ▾Hide ▴
Evidence considered
  • No trans observation data.
Still missing
  • No observation in trans with dominant pathogenic variant.
BP5 No observation of this variant in a case with an alternate molecular basis for disease is available. Details ▾Hide ▴
Evidence considered
  • No alternate molecular basis data.
Still missing
  • No observation with alternate molecular cause.
Not applicable · 7· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_033084.4:c.70A>G is a missense variant (p.Arg24Gly) and does not fall into the PVS1 null-variant buckets (nonsense, frameshift, or canonical ±1,2 splice consensus variants). Generic PVS1 framework is not applicable. Details ▾Hide ▴
Evidence considered
  • Missense variant
  • variant bucket 'other' per PVS1 variant assessment
  • generic PVS1 framework not applied.
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PM3 N/ANo observation of this variant in trans with a known pathogenic variant in FANCD2 for this recessive disorder. Details ▾Hide ▴

No further detail was recorded.

PM4 N/AThis is a missense substitution (p.Arg24Gly). PM4 applies only to non-repeat protein length changes (in-frame deletions/insertions, stop-loss). Details ▾Hide ▴

No further detail was recorded.

PM5 N/ANo known pathogenic missense variant at the same residue (Arg24) with a different amino acid change was identified to serve as a PM5 comparator. Candidate harvesting was unsuccessful. Details ▾Hide ▴
Evidence considered
  • PM5 candidate search: no same-residue pathogenic comparators found. Unable to confirm classic same-residue PM5 semantics.
Sources
pm5_candidates
BP1 N/AFANCD2 is associated with both truncating and missense pathogenic variants in Fanconi anemia. BP1 applies only when the disease mechanism is exclusively via truncating variants. Details ▾Hide ▴
Evidence considered
  • FANCD2 loss-of-function mechanism supported
  • but both truncating and missense variants are documented as pathogenic.
Sources
pvs1_gene_context
BP3 N/AThis variant is a substitution. BP3 applies only to in-frame insertions/deletions in repetitive regions. Details ▾Hide ▴

No further detail was recorded.

BP7 N/AThis is a missense variant (c.70A>G, p.Arg24Gly). BP7 applies only to synonymous or intronic variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
  • Missense substitution
  • BP7 not applicable.

Identifiers

Gene
FANCD2
Transcript
NM_033084.4
Coding (HGVS c.)
NM_033084.4:c.70A>G
Protein (HGVS p.)
NP_149075.2:p.(Arg24Gly)
GRCh38
chr3:10032837 A>G
GRCh37
chr3:10074521 A>G
ClinVar
1692057

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…
gnomAD v4.1 5 / 1,612,676 alleles AF 3.1e-06 · 0 homozygotes · FAF 1.24e-06
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 3.1e-06 · 5 / 1,612,676 alleles · 0 hom · FAF 1.2e-06
European (non-Finnish)5 / 1,179,324 4.2e-06
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 3.10044e-06; MAF= 0.00031%, 5/1612676 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 4.23972e-06; MAF= 0.00042%, 5/1179324 alleles, homozygotes = 0); grpmax FAF= 1.24e-06.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat +2 bp
0.080
SpliceAI acceptor gainat -5 bp
0.000
SpliceAI donor lossat +2 bp
0.000
SpliceAI donor gainat -414 bp
0.000
Pangolin splice lossmagnitude shown
-0.050
Pangolin splice gain
0.020

Other predictors

REVEL
0.023
BayesDel
-0.631

How the predictions were used

BP4 SupportingMultiple lines of computational evidence support a benign interpretation: REVEL score 0.023 (strongly benign), BayesDel score -0.631 (benign), and SpliceAI max delta 0.08 (no splicing impact). All in silico predictors are concordant for no impact on gene product. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.023 (strongly benign). BayesDel: -0.631 (benign). SpliceAI: max delta 0.08 (no splicing impact). All predictors concordant for benign interpretation.
Sources
revelbayesdelspliceai ↗
PP3 Multiple lines of computational evidence do not support a deleterious effect: REVEL score 0.023 (strongly benign), BayesDel score -0.631 (benign), and SpliceAI max delta 0.08 (no splicing impact). All in silico predictors are concordant for a benign interpretation. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.023 (strongly benign). BayesDel: -0.631 (benign). SpliceAI: max delta 0.08 (no splicing impact). All predictors concordant for benign.
Sources
revelbayesdelspliceai ↗
BP7 N/AThis is a missense variant (c.70A>G, p.Arg24Gly). BP7 applies only to synonymous or intronic variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
  • Missense substitution
  • BP7 not applicable.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.08). REVEL score = 0.023. BayesDel score = -0.631389.

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

  • Carrier screening in individuals of Ashkenazi Jewish descent.
    Gross SJ et al. · 2008
    ACMG guideline on carrier screening for genetic disorders in individuals of Ashkenazi Jewish descent. Discusses disease panels including Tay-Sachs, cystic fibrosis, and familial dysautonomia. FANCD2 and NM_033084.4:c.70A>G were not mentioned.
    Does not name this variant
    PMID 18197057 ↗
  • Fanconi Anemia.
    Adam MP et al. · 1993
    GeneReviews entry for Fanconi anemia providing broad clinical and genetic overview of FA genes including FANCD2. No mention of the specific variant NM_033084.4:c.70A>G (p.Arg24Gly).
    Does not name this variant
    PMID 20301575 ↗
  • Genetics of Breast and Gynecologic Cancers (PDQ®): Health Professional Version.
    PDQ Cancer Genetics Editorial Board · 2002
    PDQ cancer genetics summary on breast and gynecologic cancer predisposition. Discusses hereditary cancer genes at a general level. NM_033084.4:c.70A>G was not mentioned.
    Does not name this variant
    PMID 26389210 ↗
  • Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Version.
    PDQ Cancer Genetics Editorial Board · 2002
    PDQ summary on cancer genetics risk assessment and counseling. Covers general principles of hereditary cancer evaluation. NM_033084.4:c.70A>G was not mentioned.
    Does not name this variant
    PMID 26389258 ↗
  • Genetics of Skin Cancer (PDQ®): Health Professional Version.
    PDQ Cancer Genetics Editorial Board · 2002
    PDQ summary on genetics of skin cancer. Discusses melanoma and non-melanoma skin cancer predisposition genes. NM_033084.4:c.70A>G and FANCD2 were not mentioned.
    Does not name this variant
    PMID 26389333 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 5 / 1,612,676 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.080 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

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= 3.10044e-06; MAF= 0.00031%, 5/1612676 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 4.23972e-06; MAF= 0.00042%, 5/1179324 alleles, homozygotes = 0); grpmax FAF= 1.24e-06.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar but submission details could not be extracted. (ClinVarID = 1692057)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.08). REVEL score = 0.023. BayesDel score = -0.631389.

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.