NM_033084.4:c.2255T>C

FANCD2 · NP_149075.2:p.(Ile752Thr) · NM_033084.4

GRCh37: chr3:10107164 T>C · GRCh38: chr3:10065480 T>C

Gene: FANCD2 Transcript: NM_033084.4

Final call

VUS

PM2 moderate

Variant details

Gene

FANCD2

Transcript

NM_033084.4

Protein

NP_149075.2:p.(Ile752Thr)

gnomAD AF

4.352459699332084e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

PM2 (Moderate): the allele is extremely rare in population databases (overall AF 4.35e-06, max ancestry-specific AF 2.23e-05, no homozygotes), meeting the PM2 moderate threshold.

With only this single moderate criterion met, no ACMG/AMP 2015 combination rule is satisfied, and the variant is classified as a variant of uncertain significance (VUS).

Final determination: Generic ACMG/AMP 2015 fallback: 1 PM2 (moderate) alone does not meet any Pathogenic/Likely Pathogenic/Benign/Likely Benign combination rule, so the variant is classified as 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	Not applicable: this is a missense substitution, so no null-variant mechanism such as nonsense-mediated decay applies.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: no established pathogenic variant producing the identical amino-acid change (p.Ile752Thr) was identified.	pm5_candidates
PS2	Not assessed	Not assessed: no parental testing or confirmed de novo observation is available for this variant.
PS3	Not assessed	Not assessed: no functional or experimental studies of p.Ile752Thr were available.
PS4	Not assessed	Not assessed: no case-control study or affected-case counts for this variant were provided.	PMID:19888064
PM1	Not assessed	Not assessed: no well-established mutational hotspot or functional-domain annotation covering residue 752 was available.	oncokb
PM2	Met	Met (Moderate): allele extremely rare in population databases (overall AF 4.35e-06; max ancestry-specific 2.23e-05), absent from gnomAD v2.1, with no homozygotes.	gnomad_v2 gnomad_v4 gnomad_canada
PM3	Not assessed	Not assessed: no affected-proband observation with a pathogenic FANCD2 variant or phase information was available.	generic_acmg_combination_rules
PM4	N/A	Not applicable: this missense substitution does not alter protein length, so there is nothing for the criterion to evaluate.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no different missense change at residue 752 with an established pathogenic classification was identified.	pm5_candidates
PM6	Not assessed	Not assessed: no de novo occurrence without confirmed parentage was reported for this variant.
PP1	Not assessed	Not assessed: no informative family segregation data were available.
PP2	Not assessed	Not assessed: no missense-constraint metric (e.g., gnomAD missense Z-score) was available to assess FANCD2's tolerance to missense variation.	pvs1_gene_context
PP3	Not met	Not met: REVEL score 0.578 falls in the gray zone (0.250-0.750), below the PP3 threshold.	revel
PP4	Not assessed	Not assessed: no phenotype or clinical findings for a carrier of this variant were provided.	clinvar
PP5	Not met	Not met: the sole ClinVar submission is classified as uncertain significance, with no expert-panel assertion.	clinvar
BA1	Not met	Not met: highest observed population allele frequency is 4.35e-05, far below the stand-alone benign threshold.	gnomad_v4
BS1	Not met	Not met: observed population allele frequencies (max 2.23e-05) are far too low to support a benign classification.	gnomad_v4
BS2	Not met	Not met: no homozygotes are observed in gnomAD v4.1, so no unaffected-individual observations support BS2.	gnomad_v4
BS3	Not assessed	Not assessed: no functional studies were available to show a validated assay detected no damaging effect.
BS4	Not assessed	Not assessed: no non-segregation evidence is available for this variant.
BP1	Not assessed	Not assessed: available evidence could not establish that FANCD2 disease is caused primarily by truncating variants.	pvs1_gene_context
BP2	Not assessed	Not assessed: no cis or trans observation with a pathogenic FANCD2 variant was documented.	generic_acmg_combination_rules
BP3	N/A	Not applicable: this missense substitution does not alter protein length within a repeat region.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: REVEL score 0.578 is above the BP4 threshold (REVEL < 0.250).	revel
BP5	Not assessed	Not assessed: no alternative molecular cause explaining the phenotype was documented.
BP6	Not met	Not met: the sole ClinVar submission is uncertain significance, with no expert-panel benign assertion.	clinvar
BP7	N/A	Not applicable: this is a missense substitution, not a synonymous variant, so the criterion does not apply.	generic_acmg_combination_rules

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