NM_033084.4:c.266A>G

FANCD2 · NP_149075.2:p.(Tyr89Cys) · NM_033084.4

GRCh37: chr3:10076213 A>G · GRCh38: chr3:10034529 A>G

Gene: FANCD2 Transcript: NM_033084.4

Final call

VUS

PM2 moderate BP4 supporting benign

Variant details

Gene

FANCD2

Transcript

NM_033084.4

Protein

NP_149075.2:p.(Tyr89Cys)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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).

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	PVS1 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).	pvs1_generic_framework pvs1_variant_assessment
PS1	Not assessed	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.	clinvar
PS2	Not assessed	No de novo observation with confirmed paternity and maternity has been reported for this variant. The variant is absent from ClinVar and the literature.	clinvar
PS3	Not assessed	No well-established in vitro or in vivo functional studies have been identified for this variant. OncoKB reports no variant-specific reviewed functional evidence.	oncokb
PS4	Not assessed	No case-control or prevalence data are available. The variant is absent from ClinVar and has not been reported in any affected cohorts.	clinvar
PS5	Not met	No reputable source has classified this variant as pathogenic or likely pathogenic. The variant is entirely absent from ClinVar.	clinvar
PM1	Not assessed	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.	oncokb
PM2	Met	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.	gnomad_v2 gnomad_v4
PM5	N/A	No 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.	pm5_candidates clinvar
PM6	Not assessed	No assumed de novo observation (without confirmation of paternity and maternity) has been reported for this variant.	clinvar
PP1	Not assessed	No cosegregation data are available for this variant. No family studies have been reported.
PP2	Not assessed	HCI Prior score is not available for FANCD2 (gene not supported by the HCI predictor), precluding assessment of missense constraint (z-score).
PP3	Not met	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).	revel bayesdel spliceai
PP4	Not assessed	No patient phenotype or family history data are available for this variant. The variant has not been reported in any clinical context.
PP5	Not met	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.	clinvar
BA1	Not met	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).	gnomad_v2 gnomad_v4
BS1	Not met	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).	gnomad_v2 gnomad_v4
BS2	Not assessed	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	Not assessed	No well-established functional studies demonstrating no damaging effect have been identified for this variant.	oncokb
BS4	Not assessed	No segregation data in affected families are available to assess lack of cosegregation with disease.
BP1	N/A	FANCD2 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.	pvs1_gene_context
BP2	Not assessed	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.
BP3	N/A	This is a single-nucleotide substitution, not an in-frame deletion/insertion in a repetitive region. BP3 does not apply.
BP4	Met	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 bayesdel spliceai
BP5	Not assessed	No data are available regarding an alternative molecular basis for disease in a case carrying this variant.
BP6	Not assessed	No reputable source has reported this variant as benign or likely benign. The variant is absent from ClinVar.	clinvar
BP7	N/A	BP7 applies to synonymous (silent) variants with no predicted splice impact. This variant is a missense substitution (p.Tyr89Cys) and is not silent.

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