NM_001184.3:c.2804A>C

ATR · NP_001175.2:p.(Gln935Pro) · NM_001184.3

GRCh37: chr3:142272070 T>G · GRCh38: chr3:142553228 T>G

Gene: ATR Transcript: NM_001184.3

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

ATR

Transcript

NM_001184.3

Protein

NP_001175.2:p.(Gln935Pro)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

PM2 (supporting): NM_001184.3:c.2804A>C is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, consistent with a rare variant not observed in population databases.

BP4 (supporting): Multiple in silico predictors do not support a deleterious effect. SpliceAI max delta is 0.17 (no predicted splicing impact). BayesDel score is 0.216 (below deleterious threshold). REVEL score is 0.52 (indeterminate).

Classification: Uncertain Significance (VUS). One supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4) result in equivocal evidence. No other criteria were met in either the pathogenic or benign direction.

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	NM_001184.3:c.2804A>C is a missense substitution (p.Gln935Pro) and does not fall into the generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants per ClinGen SVI PVS1 recommendations (PMC6185798).	pvs1_variant_assessment pvs1_generic_framework
PS1	Not met	No different pathogenic missense variant at the same amino acid position (Gln935) has been reported in ClinVar or the literature. PS1 requires a different nucleotide change at the same codon resulting in the same amino acid change, or evidence of a different pathogenic missense at the same codon.	clinvar
PS2	Not met	No de novo data are available for this variant. Neither ClinVar submissions nor the literature search returned any de novo reports for NM_001184.3:c.2804A>C.
PS3	Not met	No variant-specific functional data are available. OncoKB classifies this variant as Unknown Oncogenic Effect with no curated functional evidence. No publications with experimental functional characterization of NM_001184.3:c.2804A>C were identified in the literature search.	oncokb
PS4	Not met	No case-control or prevalence data are available for this variant. The variant is absent from ClinVar and has not been reported in any clinical case series or cohort studies.	clinvar
PS5	Not met	PS5 requires two or more independent sources reporting the variant in affected individuals. No sources — ClinVar, literature, or other databases — have reported this variant in any affected individual.
PM1	Not met	Position 935 in ATR lies in the N-terminal region of the protein, outside the characterized C-terminal kinase domain (PIKK domain, approximately residues 2300–2600). Cancerhotspots.org does not identify this residue as a statistically significant mutational hotspot. No domain-level functional characterization specifically implicating residue 935 in a critical functional domain was identified.
PM2	Met	NM_001184.3:c.2804A>C is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes), meeting the PM2 threshold for absence from population databases (<0.1%).	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	No same-residue comparator variants identified. PM5 candidate harvesting was unable to confirm classic same-residue PM5 semantics; no ClinVar entries exist at position Gln935 for ATR.	pm5_candidates
PM6	Not met	No de novo reports are available. The literature search returned zero PMIDs mentioning this variant, and ClinVar has no submissions for this variant. PM6 requires a confirmed de novo observation with maternity and paternity confirmed.
PP1	Not met	No segregation data are available. No family studies including this variant have been reported in ClinVar or the literature.
PP2	Not met	PP2 applies when missense variation is a common disease mechanism and the gene has a low rate of benign missense variation. ATR has a relatively high background rate of missense variation in population databases and no ClinGen CSPEC/VCEP specification for missense constraint is available. Insufficient evidence to assert that missense variants in ATR meet the PP2 threshold under generic ACMG.
PP3	Not met	Multiple lines of computational evidence do not support a deleterious effect. REVEL score is 0.52 (indeterminate, below typical pathogenic threshold of 0.75). BayesDel score is 0.216 (below typical deleterious threshold). SpliceAI max delta is 0.17 (no predicted splicing impact, below 0.2 threshold). Taken together, these in silico predictors do not meet the threshold for PP3.	revel bayesdel spliceai
PP4	Not met	No phenotype or family history data are available for the proband. PP4 requires that the patient phenotype or family history is highly specific for the disease associated with the gene.
PP5	Not met	This variant is absent from ClinVar. No expert panel or reputable source has classified this variant as pathogenic or likely pathogenic.	clinvar
BA1	Not met	BA1 requires an allele frequency >1% in a population database. NM_001184.3:c.2804A>C is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, far below the BA1 threshold.	gnomad_v2 gnomad_v4
BS1	Not met	BS1 requires an allele frequency >0.3% in a population database. NM_001184.3:c.2804A>C is absent from all gnomAD datasets, far below the BS1 threshold.	gnomad_v2 gnomad_v4
BS2	Not met	BS2 requires observation of the variant in healthy adults in a homozygous state, or in trans with a pathogenic variant with full penetrance expected early in life. No such observations are available for this variant.
BS3	Not met	No functional studies demonstrating a benign effect for this variant are available. No experimental characterization of p.Gln935Pro or systematic functional assessment of the region including residue 935 has been reported.
BS4	Not met	No segregation data showing lack of co-segregation with disease are available. BS4 requires observation of the variant in a family member without the disease phenotype.
BP1	Not met	BP1 applies when a missense variant occurs in a gene where primarily truncating variants are known to cause disease. While ATR loss of function is a supported disease mechanism, there is insufficient evidence to assert that missense variants in ATR are categorically benign. No ClinGen CSPEC/VCEP specification exists to apply BP1 to ATR missense variants.	pvs1_gene_context
BP2	Not met	BP2 requires observation of the variant in trans with a known pathogenic variant in a gene associated with a fully penetrant recessive disorder. No such observation is available. ATR-associated disease is not established as a recessive disorder with full penetrance expected early in life.
BP4	Met	Multiple lines of computational evidence suggest no deleterious impact. SpliceAI predicts no significant splicing effect (max delta score 0.17, below 0.2 threshold). BayesDel score is 0.216, below the typical deleterious threshold. REVEL score is 0.52 (indeterminate, does not support a pathogenic classification). The aggregate in silico evidence does not support a damaging effect on the gene product.	spliceai revel bayesdel
BP5	Not met	BP5 requires the variant to be observed in a case with an alternate molecular basis for disease. No such observation has been reported for this variant.
BP6	Not met	This variant is absent from ClinVar. No expert panel or reputable source has classified this variant as benign or likely benign. BP6 cannot be applied without a trusted source classification.	clinvar
BP7	N/A	NM_001184.3:c.2804A>C is a missense substitution resulting in p.Gln935Pro. BP7 applies only to synonymous variants with no predicted splice impact and is not applicable to missense variants.

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