Classification rationale

PM2 BP4 VUS

FANCD2 c.2038G>A

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.¹ 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.²

PM2 + BP4 → VUS

1 gnomad_v2 ↗gnomad_v4 ↗revelbayesdelspliceai ↗clinvar ↗

2 generic_acmg_combination_rules

Gene diagram · NM_033084.4 · variants mapped to exon structure

FANCD2 NM_033084.4

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 21 assessed

Applied · 2

Strength Supporting Moderate Strong Very strong

✓

PM2 supporting Pathogenic

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).

Absent from gnomAD v2.1 (exomes)Absent from gnomAD v4.1 (exomes)Absent from gnomAD-Canada v1.0

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

✓

BP4 supporting Benign

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.

REVEL: 0.122 (benign-range)BayesDel: -0.267817 (benign-range)SpliceAI max delta: 0.01 (no splicing impact)

spliceai ↗

Assessed · not applied

Pathogenic

PS1 No same amino acid change (p.Val680Met) arising from a different nucleotide substitution has been reported as pathogenic in ClinVar or the literature.

PS2 No de novo confirmation data are available for this variant.

PS3 No variant-specific functional data identified.

PS4 No case-control or cohort data demonstrate enrichment of this variant in affected individuals versus controls.

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.

PM5 No same-residue comparator missense variant at p.Val680 previously established as pathogenic was identified.

PM6 No de novo event has been reported for this variant.

PP1 No cosegregation data are available for this variant.

PP2 The HCI prior (missense constraint) score is unavailable for FANCD2 (gene_not_supported).

PP3 Multiple in silico tools predict a benign effect.

PP4 No phenotype or clinical data are available for an individual carrying this variant.

PP5 This variant is absent from ClinVar entirely.

Benign

BA1 This variant is absent from gnomAD.

BS1 This variant is absent from gnomAD.

BS2 No data are available on homozygous occurrence or observation in healthy adult controls.

BS3 No functional studies demonstrating a benign effect have been performed for this variant.

BS4 No segregation data are available to demonstrate lack of cosegregation with disease.

BP1 BP1 requires that a gene is known to cause disease exclusively through truncating variants.

BP2 No observation of this variant in trans with a known pathogenic FANCD2 variant has been reported.

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.

BP6 This variant is absent from ClinVar.

N/A · 5 PVS1 · PM3 · PM4 · BP3 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

Absent from gnomAD v4.1.

v2.1

Absent from gnomAD v2.1.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant is absent from ClinVar.

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.

SpliceAI ↗

Functional Unknown Oncogenic Effect

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

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots