NM_001184.3:c.1751A>G

ATR · NP_001175.2:p.(Asp584Gly) · NM_001184.3

GRCh37: chr3:142277600 T>C · GRCh38: chr3:142558758 T>C

Gene: ATR Transcript: NM_001184.3

Final call

VUS

PM2 supporting BP4 supporting benign

Variant details

Gene

ATR

Transcript

NM_001184.3

Protein

NP_001175.2:p.(Asp584Gly)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_001184.3:c.1751A>G (p.Asp584Gly) is absent from all population databases including gnomAD v2.1, v4.1, and gnomAD-Canada, meeting PM2 at supporting strength.

Multiple computational predictors suggest a benign effect: REVEL score 0.11 and BayesDel score -0.208 both predict no deleterious impact, meeting BP4 at supporting benign strength.

SpliceAI max delta score is 0.33 (acceptor loss 0.33, donor loss 0.30), which is borderline above the 0.2 threshold, but Pangolin splice loss score of -0.31 predicts no splice-altering effect. The in silico consensus favors a neutral interpretation.

No functional data, no published cases, no ClinVar classifications, and no segregation data are available for this variant. All remaining pathogenic and benign criteria are not met.

With one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4), the evidence is balanced. The variant is classified as a Variant of Uncertain Significance (VUS) per ACMG/AMP 2015 combination rules.

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.1751A>G is a missense variant (p.Asp584Gly) and does not fall into any generic PVS1 null-variant bucket (nonsense, frameshift, or canonical ±1,2 splice consensus). The ClinGen SVI PVS1 framework (PMC6185798) does not apply to missense substitutions in the absence of a demonstrated effect on splicing at the RNA level.	pvs1_generic_framework pvs1_variant_assessment pvs1_gene_context
PS1	Not met	No alternative nucleotide change resulting in the same amino acid substitution (p.Asp584Gly) has been reported as pathogenic. The variant is absent from ClinVar, and no literature reports a different nucleotide change at this codon with an established pathogenic classification.	clinvar
PS2	Not met	No de novo occurrence has been reported for this variant. No publications mention NM_001184.3:c.1751A>G, and no family studies with confirmed parentage are available.
PS3	Not met	No functional data exist for NM_001184.3:c.1751A>G (p.Asp584Gly). OncoKB classifies this variant as 'Unknown Oncogenic Effect' with no variant-specific curated functional evidence. No publications with functional characterization were identified. The variant is absent from COSMIC and has not been studied in any experimental system.	oncokb
PS4	Not met	The variant has not been observed in any affected individuals. It is absent from ClinVar, absent from gnomAD, and absent from all publications. No case-control or odds-ratio analysis is possible for a variant with zero observations.	gnomad_v2 gnomad_v4 clinvar
PS5	N/A	PS5 is not a criterion in the standard ACMG/AMP 2015 classification framework (PMID:25741868). The established pathogenic criteria are PVS1, PS1–PS4, PM1–PM6, and PP1–PP5. No VCEP/CSPEC framework is available for ATR to define an extended PS5 criterion.	generic_acmg_combination_rules
PM1	Not met	Residue Asp584 is not located in a statistically significant mutational hotspot (cancerhotspots.org negative). No evidence was identified that this specific residue lies within a well-characterized functional domain where missense variants are an established pathogenic mechanism for germline ATR-related disease.	pvs1_gene_context
PM2	Met	NM_001184.3:c.1751A>G is absent from large population databases including gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes). In the generic ACMG/AMP 2015 framework, absence from population databases supports pathogenicity at supporting strength when the variant is not observed in a large number of ethnically diverse individuals.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not met	No pathogenic missense variant at the same amino acid residue (Asp584) has been identified. The PM5 candidate search returned zero comparators. ClinVar has no entries for any missense change at codon 584 of ATR. No literature reports describe a different pathogenic amino acid change at this position.	pm5_candidates clinvar
PM6	Not met	No de novo occurrence has been reported for this variant. No publications describe a de novo ATR c.1751A>G event with confirmed maternity and paternity. No ClinVar submissions assert de novo status.	clinvar
PP1	Not met	No segregation data are available. The variant has not been identified in any family, and no co-segregation analysis with disease phenotype has been performed.	clinvar
PP2	Not met	While ATR loss of function is supported as a germline disease mechanism, there is insufficient evidence that ATR has a low rate of benign missense variation and that missense variants are a common mechanism of disease. Missense constraint metrics (e.g., gnomAD missense Z-score) were not provided, and the HCI prior score was not found.	pvs1_gene_context
PP3	Not met	Multiple computational predictors do not support a deleterious effect. REVEL score is 0.11 (predicts benign), BayesDel score is -0.208 (predicts benign). SpliceAI max delta score is 0.33 (acceptor loss 0.33, donor loss 0.30), which is above the 0.2 threshold, but the Pangolin splice loss score is -0.31 (predicts no splice-altering effect). The preponderance of in silico evidence favors a neutral effect.	revel bayesdel spliceai
PP4	Not met	No patient with this variant and a phenotype specific for ATR-related disease has been reported. The variant has not been observed in any individual, precluding phenotype-specificity assessment.	clinvar
PP5	Not met	The variant is absent from ClinVar. No reputable source has reported this variant as pathogenic. In the absence of any classification, PP5 cannot be applied.	clinvar
BA1	Not met	The variant is absent from gnomAD (allele frequency = 0). BA1 requires an allele frequency >5% (or >1% depending on framework) in population databases, which is not met when the variant is entirely absent.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	The variant is absent from gnomAD (allele frequency = 0). BS1 requires the allele frequency to be greater than expected for the disorder prevalence (typically >0.3% for rare dominant disorders in generic ACMG). A frequency of zero does not satisfy BS1; absence from population databases supports PM2, not BS1.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	The variant has not been observed in any individual, healthy or affected. BS2 requires observation in a healthy adult individual for a fully penetrant disorder expected to manifest at an early age. Without any observations, BS2 cannot be evaluated.	gnomad_v2 gnomad_v4 clinvar
BS3	Not met	No functional studies have been performed on this variant. BS3 requires well-established in vitro or in vivo functional studies demonstrating no damaging effect on protein function or splicing. No such studies exist for p.Asp584Gly.	oncokb
BS4	Not met	No segregation data are available for this variant. BS4 requires lack of segregation in affected family members. No families with this variant have been identified.	clinvar
BP1	Not met	BP1 applies to missense variants in genes where truncating variants are the only known cause of disease. While ATR loss-of-function is supported as a germline disease mechanism, insufficient evidence exists to conclude that missense variants cannot also be pathogenic. No gene-specific framework restricts ATR pathogenicity exclusively to truncating variants.	pvs1_gene_context
BP2	Not met	The variant has not been observed in any individual. BP2 requires observation in trans with a known pathogenic variant (for fully penetrant dominant disorders) or in cis with a pathogenic variant (for recessive disorders). No co-occurrence data are available.	clinvar
BP4	Met	Multiple lines of computational evidence suggest no impact on the gene product. REVEL score is 0.11 (predicts benign, below the standard 0.5 threshold). BayesDel score is -0.208 (negative, predicts benign). While SpliceAI max delta is 0.33 (borderline above 0.2), the Pangolin splice loss score is -0.31 (predicts no splice-altering effect). The preponderance of in silico evidence supports a benign interpretation at supporting strength.	revel bayesdel spliceai
BP5	Not met	No alternative molecular basis for disease has been identified in an individual carrying this variant. BP5 requires a case where an alternate cause of disease is found while this variant is also present, which has not been reported.
BP6	Not met	The variant is absent from ClinVar. BP6 requires a reputable source to have recently reported the variant as benign. No such classification exists.	clinvar
BP7	N/A	BP7 applies specifically to synonymous (silent) variants for which splicing prediction algorithms predict no impact and the nucleotide is not highly conserved. NM_001184.3:c.1751A>G is a missense variant (p.Asp584Gly), not a synonymous variant. BP7 is not applicable to missense substitutions.	generic_acmg_combination_rules

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