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FANCD2c.2038G>AUncertain significance
Print report
Variant interpretation report

FANCD2 c.2038G>A, p.(Val680Met)

NM_033084.4:c.2038G>A NP_149075.2:p.(Val680Met) 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

This variant is absent from gnomAD v2.1 and v4.1, meeting the PM2 threshold for a rare variant (allele frequency <0.1% in all populations).

Benign criteria applied · 1
BP4Supporting
BP4 · supporting

Multiple lines of in silico computational evidence predict a benign effect for this missense variant. REVEL score is 0.122 (benign-range). BayesDel score is -0.267817 (benign-range). SpliceAI predicts no splicing impact (max delta = 0.01). No computational tool supports a damaging prediction.

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; 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
0.010 maximum delta

Recorded SpliceAI maximum delta score: 0.010. 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 · 22 not met · 0 not assessed · 5 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.2038G>A (p.Val680Met) is a missense variant in FANCD2 that is absent from gnomAD population databases (PM2_supporting). Multiple in silico tools predict a benign effect: REVEL score 0.122, BayesDel score -0.267817, and SpliceAI max delta 0.01 (BP4_supporting). No variant-specific functional data, clinical reports, segregation data, or ClinVar entries exist. The variant has not been reported in the literature.

The evidence for pathogenicity (PM2_supporting) is counterbalanced by evidence against pathogenicity (BP4_supporting). With only one supporting pathogenic criterion and one supporting benign criterion, the variant is classified as a Variant of Uncertain Significance (VUS) per ACMG/AMP 2015 guidelines.

Met · 2

PM2 SupportingThis variant is absent from gnomAD v2.1 and v4.1, meeting the PM2 threshold for a rare variant (allele frequency <0.1% in all populations). Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 (exomes)
  • Absent from gnomAD v4.1 (exomes)
  • Absent from gnomAD-Canada v1.0
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BP4 SupportingMultiple lines of in silico computational evidence predict a benign effect for this missense variant. REVEL score is 0.122 (benign-range). BayesDel score is -0.267817 (benign-range). SpliceAI predicts no splicing impact (max delta = 0.01). No computational tool supports a damaging prediction. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.122 (benign-range)
  • BayesDel: -0.267817 (benign-range)
  • SpliceAI max delta: 0.01 (no splicing impact)
Sources
revelbayesdelspliceai ↗

Not met · 22 · evaluated, threshold not reached

PS1 No same amino acid change (p.Val680Met) arising from a different nucleotide substitution has been reported as pathogenic in ClinVar or the literature. Details ▾Hide ▴
Evidence considered
  • ClinVar contains no entries for this variant at any nucleotide change
  • No published pathogenic variant with the same amino acid change identified
Still missing
  • No functional or clinical data on alternative nucleotide changes producing V680M
Sources
clinvar ↗
PS2 No de novo confirmation data are available for this variant. No parentage testing or de novo observation has been reported. Details ▾Hide ▴
Evidence considered
  • No de novo event reported in any source reviewed
Still missing
  • No family or parentage data available
PS3 No variant-specific functional data identified. OncoKB reports Unknown Oncogenic Effect with no curated functional evidence for this variant. No experimental studies testing p.Val680Met were found in any reviewed source. Details ▾Hide ▴
Evidence considered
  • OncoKB classification: Unknown Oncogenic Effect
  • No functional studies identified for this variant in any reviewed source
Still missing
  • No functional characterization of p.Val680Met has been performed
Sources
oncokb ↗
PS4 No case-control or cohort data demonstrate enrichment of this variant in affected individuals versus controls. The variant is absent from population databases but no affected probands have been reported. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 and v4.1
  • No affected proband count or case-control comparison available
Still missing
  • No clinical cohort or case-control data for this variant
Sources
gnomad_v2 ↗gnomad_v4 ↗
PM1 This variant (p.Val680Met) is not located in a statistically significant mutational hotspot as assessed by cancerhotspots.org, and no well-characterized functional domain has been specifically mapped to this residue in the literature sufficient to support PM1. Details ▾Hide ▴
Evidence considered
  • CancerHotspots: not a significant residue-level hotspot
  • Residue 680 is in exon 23
  • no domain-level functional characterization targeting this residue identified
Still missing
  • No functional domain annotation for residue 680
PM5 No same-residue comparator missense variant at p.Val680 previously established as pathogenic was identified. The PM5 candidate search returned zero candidates. Without a pathogenic comparator at the same residue, PM5 cannot be applied. Details ▾Hide ▴
Evidence considered
  • PM5 candidate search: 0 same-residue candidates found
  • ClinVar contains no pathogenic missense variants at residue 680
Still missing
  • No pathogenic comparator variant at residue 680 exists to satisfy PM5
Sources
pm5_candidates
PM6 No de novo event has been reported for this variant. No maternity/paternity confirmation or de novo observation exists in any reviewed source. Details ▾Hide ▴
Evidence considered
  • No de novo report identified in ClinVar
  • literature
  • or other sources
Still missing
  • No parental testing or de novo data available
PP1 No cosegregation data are available for this variant. No family studies have been reported. Details ▾Hide ▴
Evidence considered
  • No family segregation data available
Still missing
  • No cosegregation analysis performed
PP2 The HCI prior (missense constraint) score is unavailable for FANCD2 (gene_not_supported). Without evidence that FANCD2 has a low rate of benign missense variation and that missense variants are a common mechanism of disease, PP2 cannot be applied. Details ▾Hide ▴
Evidence considered
  • HCI prior not available for FANCD2
Still missing
  • No missense constraint data (HCI prior) for FANCD2
PP3 Multiple in silico tools predict a benign effect. REVEL score is 0.122 (benign-range, well below 0.5 threshold). BayesDel score is -0.267817 (benign-range, negative). SpliceAI max delta is 0.01 indicating no splicing impact. In silico predictions do not support a damaging effect. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.122 (benign-range)
  • BayesDel: -0.267817 (benign-range)
  • SpliceAI max delta: 0.01 (no splicing impact)
Sources
revelbayesdelspliceai ↗
PP4 No phenotype or clinical data are available for an individual carrying this variant. The variant has not been reported in any affected proband. Details ▾Hide ▴
Evidence considered
  • No proband phenotype or clinical presentation data available
Still missing
  • No clinical phenotype data for any carrier of this variant
PP5 This variant is absent from ClinVar entirely. No reputable source has classified it as pathogenic. PP5 requires a ClinVar entry with at least 3-star expert panel review status, which does not exist for this variant. Details ▾Hide ▴
Evidence considered
  • ClinVar: no entries
  • no classification
  • no review status
Still missing
  • Variant has not been submitted to ClinVar
Sources
clinvar ↗
BA1 This variant is absent from gnomAD. The allele frequency is 0%, which does not meet the BA1 threshold of >1% in any population. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 and v4.1
  • allele frequency 0%
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 This variant is absent from gnomAD. The allele frequency is 0%, which does not meet the BS1 threshold of >0.3% in any population. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 and v4.1
  • allele frequency 0%
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS2 No data are available on homozygous occurrence or observation in healthy adult controls. The variant has not been observed in any individual. Details ▾Hide ▴
Evidence considered
  • No homozygous or control observation data available
Still missing
  • No homozygous or control cohort data
BS3 No functional studies demonstrating a benign effect have been performed for this variant. In silico predictions (REVEL 0.122, BayesDel -0.267817) are suggestive of a benign effect but do not constitute functional evidence at the BS3 level. Details ▾Hide ▴
Evidence considered
  • No experimental functional data available
  • In silico scores predict benign (REVEL 0.122
  • BayesDel -0.267817) but do not substitute for functional assays
Still missing
  • No functional assay data for this variant
Sources
revelbayesdel
BS4 No segregation data are available to demonstrate lack of cosegregation with disease. Details ▾Hide ▴
Evidence considered
  • No segregation data available
Still missing
  • No family segregation data to evaluate lack of cosegregation
BP1 BP1 requires that a gene is known to cause disease exclusively through truncating variants. While truncating FANCD2 variants are associated with Fanconi anemia and cancer predisposition, the PVS1 gene context literature also describes missense variants, and the disease mechanism is not exclusively truncating. BP1 cannot be applied. Details ▾Hide ▴
Evidence considered
  • FANCD2 disease mechanism includes both truncating and missense variant contributions
  • Gene-level literature does not support exclusive truncating mechanism
Still missing
  • Unclear whether FANCD2 disease mechanism is exclusively truncating
Sources
pvs1_gene_context
BP2 No observation of this variant in trans with a known pathogenic FANCD2 variant has been reported. Details ▾Hide ▴
Evidence considered
  • No trans-observation data available
Still missing
  • No data on co-occurrence with pathogenic FANCD2 variants
BP5 No alternative molecular cause for disease has been identified in a case carrying this variant, as no clinical case with this variant has been reported. Details ▾Hide ▴
Evidence considered
  • No clinical case with this variant reported to assess alternative etiology
Still missing
  • No proband data available
BP6 This variant is absent from ClinVar. No reputable source has classified it as benign. BP6 requires a ClinVar entry with at least 3-star expert panel review status classifying the variant as benign or likely benign. Details ▾Hide ▴
Evidence considered
  • ClinVar: no entries
  • no classification
  • no review status
Still missing
  • Variant has not been submitted to ClinVar
Sources
clinvar ↗
PS5 No variant at the same amino acid residue (p.Val680) with a different missense change has been established as pathogenic in ClinVar or the literature. No same-residue comparator candidates were identified. Details ▾Hide ▴
Evidence considered
  • PM5 candidate search returned 0 same-residue candidates
  • No pathogenic variant at residue 680 identified in ClinVar
Still missing
  • No known pathogenic variant at the Val680 residue
Sources
clinvar ↗pm5_candidates
Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant (p.Val680Met) that does not fall into the default generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants. The ClinGen SVI PVS1 decision tree (PMC6185798) does not apply to this variant class. Details ▾Hide ▴
Evidence considered
  • Missense variant NM_033084.4:c.2038G>A (p.Val680Met) in exon 23
  • Not a nonsense
  • frameshift
  • or canonical splice site variant
  • PVS1 generic framework (PMC6185798) does not apply to missense variants
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PM3 N/APM3 requires observation in trans with a pathogenic variant for recessive disorders. This assessment does not include phase data for recessive analysis. Details ▾Hide ▴
Evidence considered
  • No trans phase data available for recessive disorder assessment
PM4 N/APM4 applies to protein length-altering variants (in-frame deletions/insertions, stop-loss). This is a missense substitution. Details ▾Hide ▴
Evidence considered
  • Missense substitution
  • not a protein length-altering variant
BP3 N/ABP3 applies to in-frame deletions/insertions in repetitive regions without known function. This is a substitution variant. Details ▾Hide ▴
Evidence considered
  • Missense substitution
  • not an in-frame indel in a repetitive region
BP7 N/ABP7 applies to synonymous (silent) variants for which splicing prediction algorithms predict no impact on splicing. This is a missense variant (p.Val680Met), not a synonymous variant. Details ▾Hide ▴
Evidence considered
  • Variant is missense (p.Val680Met)
  • not synonymous

Identifiers

Gene
FANCD2
Transcript
NM_033084.4
Coding (HGVS c.)
NM_033084.4:c.2038G>A
Protein (HGVS p.)
NP_149075.2:p.(Val680Met)
GRCh38
chr3:10064745 G>A
GRCh37
chr3:10106429 G>A

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 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

SpliceAI acceptor lossat -16 bp
0.000
SpliceAI acceptor gainat +7 bp
0.010
SpliceAI donor lossat -143 bp
0.000
SpliceAI donor gainat -316 bp
0.000
Pangolin splice lossmagnitude shown
-0.010
Pangolin splice gain
0.010

Other predictors

REVEL
0.122
BayesDel
-0.268

How the predictions were used

BP4 SupportingMultiple lines of in silico computational evidence predict a benign effect for this missense variant. REVEL score is 0.122 (benign-range). BayesDel score is -0.267817 (benign-range). SpliceAI predicts no splicing impact (max delta = 0.01). No computational tool supports a damaging prediction. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.122 (benign-range)
  • BayesDel: -0.267817 (benign-range)
  • SpliceAI max delta: 0.01 (no splicing impact)
Sources
revelbayesdelspliceai ↗
PP3 Multiple in silico tools predict a benign effect. REVEL score is 0.122 (benign-range, well below 0.5 threshold). BayesDel score is -0.267817 (benign-range, negative). SpliceAI max delta is 0.01 indicating no splicing impact. In silico predictions do not support a damaging effect. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.122 (benign-range)
  • BayesDel: -0.267817 (benign-range)
  • SpliceAI max delta: 0.01 (no splicing impact)
Sources
revelbayesdelspliceai ↗
BP7 N/ABP7 applies to synonymous (silent) variants for which splicing prediction algorithms predict no impact on splicing. This is a missense variant (p.Val680Met), not a synonymous variant. Details ▾Hide ▴
Evidence considered
  • Variant is missense (p.Val680Met)
  • not synonymous

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.122. BayesDel score = -0.267817.

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 0.010 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

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 = 0.01). REVEL score = 0.122. BayesDel score = -0.267817.

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.