PM2 is met at moderate strength: the variant is absent from gnomAD v2.1 and v4.1 population databases.1 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.2 PVS1 is not applicable because this is a missense substitution (p.Tyr89Cys), not a null variant per ClinGen PVS1 recommendations (PMC6185798).3 PP3 is not met: the same in silico evidence that supports BP4 fails to support a pathogenic computational prediction.4 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.5 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).6
FANCD2
Final classification
VUS
FANCD2 c.266A>G · p.Tyr89Cys
FANCD2
PM2 is met at moderate strength: the variant is absent from gnomAD v2.1 and v4.1 population databases.
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.
Classification rationale
PM2
BP4
VUS
FANCD2 c.266A>G
PM2 + BP4
→
VUS
Gene diagram
· NM_033084.4 · variants mapped to exon structure
FANCD2
NM_033084.4
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 19 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
moderate
review
Pathogenic
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.
Absent from gnomAD v2.1 (exomes) and gnomAD v4.1 (exomes/genomes). gnomAD-Canada also shows zero allele count.
✓
BP4
supporting
Benign
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).
REVEL: 0.297BayesDel: -0.03757SpliceAI max delta: 0.02.
Assessed · not applied
Pathogenic
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.
PS2
No de novo observation with confirmed paternity and maternity has been reported for this variant.
PS3
No well-established in vitro or in vivo functional studies have been identified for this variant.
PS4
No case-control or prevalence data are available.
PM1
Residue Y89 is not located within a statistically significant mutational hotspot (CancerHotspots: no signal).
PM6
No assumed de novo observation (without confirmation of paternity and maternity) has been reported for this variant.
PP1
No cosegregation data are available for this variant.
PP2
HCI Prior score is not available for FANCD2 (gene not supported by the HCI predictor), precluding assessment of missense constraint (z-score).
PP3
Multiple lines of computational evidence do not support a deleterious effect.
PP4
No patient phenotype or family history data are available for this variant.
PP5
No reputable source has recently reported this variant as pathogenic.
Benign
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).
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).
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.
BS3
No well-established functional studies demonstrating no damaging effect have been identified for this variant.
BS4
No segregation data in affected families are available to assess lack of cosegregation with disease.
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.
BP5
No data are available regarding an alternative molecular basis for disease in a case carrying this variant.
BP6
No reputable source has reported this variant as benign or likely benign.
N/A · 5
PVS1 · PM5 · BP1 · 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
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
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
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
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.
Sources & reference links