NM_001184.3:c.6680A>G

ATR · NP_001175.2:p.(Asn2227Ser) · NM_001184.3

GRCh37: chr3:142186783 T>C · GRCh38: chr3:142467941 T>C

Gene: ATR Transcript: NM_001184.3

Final call

VUS

PM2 moderate

Variant details

Gene

ATR

Transcript

NM_001184.3

Protein

NP_001175.2:p.(Asn2227Ser)

gnomAD AF

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_001184.3:c.6680A>G (p.Asn2227Ser) is a missense variant in ATR that is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases (PM2_moderate).

No functional data, case-control studies, segregation data, or de novo observations were identified for this variant. OncoKB classifies it as Unknown Oncogenic Effect. ClinVar reports it as Uncertain significance (1★, single submitter).

In silico predictors are equivocal: REVEL 0.545 (borderline), BayesDel -0.21413 (benign), SpliceAI max delta 0.00 (no splicing impact). This does not meet PP3 or BP4 thresholds.

The only met ACMG criterion is PM2 at moderate strength (absent from population databases). No other pathogenic or benign criteria are met. Under generic ACMG/AMP 2015 combination rules (PMID:25741868), a single moderate criterion is insufficient for classification as likely pathogenic, and no benign criteria are met to offset it. The variant is classified as 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	This is a missense variant (NP_001175.2:p.Asn2227Ser); it does not fall into the default generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants per ClinGen SVI PVS1 recommendations (PMC6185798).	pvs1_generic_framework
PS1	Not met	No evidence was identified that a different nucleotide change at this position resulting in the same amino acid substitution (p.Asn2227Ser) has been previously classified as pathogenic. No same-residue comparators were found in ClinVar or the literature.	clinvar pm5_candidates
PS2	Not met	No data on de novo occurrence of this variant were identified. No parental testing results or family studies are available in the case materials.
PS3	Not met	No functional data were identified for NM_001184.3:c.6680A>G (p.Asn2227Ser) in OncoKB, the literature, or other curated sources. OncoKB classifies this variant as Unknown Oncogenic Effect. No publications with variant-specific functional assays were found.	oncokb
PS4	Not met	No case-control studies or prevalence data comparing this variant in affected vs. unaffected individuals are available. The variant has been reported only once in ClinVar as a VUS with a single clinical laboratory submission.	clinvar
PS5	N/A	PS5 is not a standard ACMG/AMP 2015 criterion and no VCEP/CSPEC framework is available for ATR that defines PS5. This case uses generic_acmg framework.	generic_acmg_combination_rules
PM1	Not met	The variant (p.Asn2227Ser) is not located in a statistically significant mutational hotspot per cancerhotspots.org. No well-characterized critical functional domain encompassing residue 2227 has been defined in the case materials, and no VCEP/CSPEC domain specification exists for ATR.
PM2	Met	The variant is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes/genomes), and gnomAD-Canada v1.0 (genomes). This satisfies the PM2 criterion (allele frequency <0.1% in large population cohorts) for a rare missense variant in ATR.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not met	No pathogenic or likely pathogenic missense variants at the same amino acid residue (p.Asn2227) were identified in ClinVar or the candidate search. The automatic PM5 candidate harvest returned zero same-residue candidates.	pm5_candidates clinvar
PM6	Not met	No de novo observation (confirmed or unconfirmed) of this variant was identified. No family studies with parental testing are available.
PP1	Not met	No co-segregation data are available for this variant. No family studies or pedigree analysis was identified in the case materials.
PP2	Not assessed	No HCI prior probability score or gene-specific missense constraint metric (e.g., missense Z-score, o/e ratio) is available for ATR in the case materials. PP2 requires evidence that the gene has a low rate of benign missense variation and that missense variants are a common disease mechanism. Without this data, PP2 cannot be reliably assessed under generic ACMG.
PP3	Not met	Multiple lines of in silico evidence do not support a deleterious effect. REVEL score is 0.545 (borderline, below the typical 0.75 pathogenic threshold), BayesDel score is -0.21413 (benign range), and SpliceAI predicts no splicing impact (max delta score = 0.00). The computational evidence is equivocal to benign and does not meet PP3.	revel bayesdel spliceai
PP4	Not met	No phenotypic data for the proband or affected individuals carrying this variant are available in the case materials. PP4 requires that the patient's phenotype or family history is highly specific for a disease with a single genetic etiology, which cannot be evaluated without clinical information.
PP5	Not met	This variant is classified as Uncertain significance in ClinVar (ClinVarID 2624947) by a single clinical laboratory with review status 'criteria provided, single submitter' (1★). PP5 requires a reputable source (≥3★ expert panel) to have classified the variant as pathogenic; 1★ VUS does not meet this threshold.	clinvar
BA1	Not met	The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. The allele frequency is 0%, which is far below the BA1 threshold of >1% in any population.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. The allele frequency is 0%, which is below the BS1 threshold of >0.3% in any population.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	No observation of this variant in a homozygous or hemizygous state in healthy adults was identified. gnomAD reports no homozygous individuals for this variant.	gnomad_v2 gnomad_v4
BS3	Not met	No well-established functional studies showing no damaging effect of this variant were identified. OncoKB reports Unknown Oncogenic Effect, and no publications with variant-specific functional assays demonstrating benign effect are available.	oncokb
BS4	Not met	No family segregation data are available to demonstrate lack of co-segregation with disease. No pedigree analysis or affected family member testing data were provided.
BP1	Not met	While ATR loss-of-function is supported as a germline disease mechanism (pvs1_gene_context: lof_mechanism_supported=true), there is insufficient evidence to conclude that missense variants in ATR are not a disease mechanism. BP1 requires demonstration that the gene primarily causes disease through truncating variants and that missense variants are a rare or unknown mechanism, which has not been established for ATR.	pvs1_gene_context
BP2	Not met	No observation of this variant in trans with a known pathogenic variant in a fully penetrant dominant disorder. ATR-associated germline disease inheritance pattern is not well-defined, and no phasing data are available.
BP4	Not met	In silico evidence is mixed and does not provide multiple consistent lines supporting no impact. REVEL score is 0.545 (borderline, neither clearly benign nor pathogenic), BayesDel is -0.21413 (benign range), and SpliceAI predicts no splicing impact (max delta 0.00). While BayesDel suggests a benign effect, REVEL is equivocal rather than clearly benign. The evidence is not sufficiently consistent across multiple predictors to meet BP4.	revel bayesdel spliceai
BP5	Not met	No alternate molecular cause for the observed phenotype was identified in the case materials. No evidence of a different pathogenic variant explaining the phenotype is available.
BP6	Not met	This variant is classified as Uncertain significance in ClinVar (ClinVarID 2624947) by a single clinical laboratory (1★). BP6 requires a reputable source (≥3★ expert panel) to have classified the variant as benign or likely benign; 1★ VUS does not meet this threshold.	clinvar
BP7	N/A	This is a missense variant (c.6680A>G, p.Asn2227Ser), not a synonymous or intronic variant. BP7 applies only to synonymous variants with no predicted splice impact.
BP3	N/A	Skipped per pre-adjudication instruction: in-frame deletion/insertion criterion not applicable to this substitution variant.
PM3	N/A	Skipped per pre-adjudication instruction: recessive disorder trans-configuration criterion not assessed.
PM4	N/A	Skipped per pre-adjudication instruction: protein length change criterion not applicable to this substitution variant.

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