NM_033084.4:c.2038G>A

FANCD2 · NP_149075.2:p.(Val680Met) · NM_033084.4

GRCh37: chr3:10106429 G>A · GRCh38: chr3:10064745 G>A

Gene: FANCD2 Transcript: NM_033084.4

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

FANCD2

Transcript

NM_033084.4

Protein

NP_149075.2:p.(Val680Met)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

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	This 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.	pvs1_generic_framework pvs1_variant_assessment
PS1	Not met	No same amino acid change (p.Val680Met) arising from a different nucleotide substitution has been reported as pathogenic in ClinVar or the literature.	clinvar
PS2	Not met	No de novo confirmation data are available for this variant. No parentage testing or de novo observation has been reported.
PS3	Not met	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.	oncokb
PS4	Not met	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.	gnomad_v2 gnomad_v4
PS5	Not met	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.	clinvar pm5_candidates
PM1	Not met	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.
PM2	Met	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).	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not met	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.	pm5_candidates
PM6	Not met	No de novo event has been reported for this variant. No maternity/paternity confirmation or de novo observation exists in any reviewed source.
BP3	N/A	BP3 applies to in-frame deletions/insertions in repetitive regions without known function. This is a substitution variant.
PM3	N/A	PM3 requires observation in trans with a pathogenic variant for recessive disorders. This assessment does not include phase data for recessive analysis.
PM4	N/A	PM4 applies to protein length-altering variants (in-frame deletions/insertions, stop-loss). This is a missense substitution.
PP1	Not met	No cosegregation data are available for this variant. No family studies have been reported.
PP2	Not met	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.
PP3	Not met	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.	revel bayesdel spliceai
PP4	Not met	No phenotype or clinical data are available for an individual carrying this variant. The variant has not been reported in any affected proband.
PP5	Not met	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.	clinvar
BA1	Not met	This variant is absent from gnomAD. The allele frequency is 0%, which does not meet the BA1 threshold of >1% in any population.	gnomad_v2 gnomad_v4
BS1	Not met	This variant is absent from gnomAD. The allele frequency is 0%, which does not meet the BS1 threshold of >0.3% in any population.	gnomad_v2 gnomad_v4
BS2	Not met	No data are available on homozygous occurrence or observation in healthy adult controls. The variant has not been observed in any individual.
BS3	Not met	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.	revel bayesdel
BS4	Not met	No segregation data are available to demonstrate lack of cosegregation with disease.
BP1	Not met	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.	pvs1_gene_context
BP2	Not met	No observation of this variant in trans with a known pathogenic FANCD2 variant has been reported.
BP4	Met	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 bayesdel spliceai
BP5	Not met	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	Not met	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.	clinvar
BP7	N/A	BP7 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.

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