NM_001184.3:c.1316A>G

ATR · NP_001175.2:p.(Asn439Ser) · NM_001184.3

GRCh37: chr3:142280118 T>C · GRCh38: chr3:142561276 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.(Asn439Ser)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

This missense variant (NM_001184.3:c.1316A>G, p.Asn439Ser) in ATR is absent from all population databases including gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, consistent with PM2 at supporting level.

Multiple in silico tools predict a benign effect: REVEL score of 0.042, BayesDel score of -0.769573, and SpliceAI max delta of 0.02 (no predicted splice alteration), consistent with BP4 at supporting benign level.

The variant is absent from ClinVar with no prior classifications, no COSMIC entries, no hotspot association, and no variant-specific functional data in OncoKB or the literature. No variant-specific publications were identified.

PVS1 is not applicable as this is a missense variant; it does not fall into the null-variant buckets defined by the ClinGen SVI PVS1 framework.

Overall, one supporting criterion toward pathogenicity (PM2) and one supporting benign criterion (BP4) are met. This does not satisfy the combination thresholds for Likely Pathogenic (≥2 supporting) or Likely Benign (≥2 supporting benign) under the generic ACMG/AMP 2015 classification rules. The variant is classified as a Variant of 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 (NM_001184.3:c.1316A>G, p.Asn439Ser) that does not fall into the ClinGen SVI PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants. PVS1 does not apply to missense substitutions under the generic ACMG/AMP framework.	pvs1_generic_framework pvs1_variant_assessment
PS1	Not met	No alternate nucleotide change at c.1316 resulting in the same N439S amino acid substitution has been reported as pathogenic. The variant is absent from ClinVar and the literature.	clinvar
PS2	Not met	No de novo occurrence data with confirmed maternity and paternity testing is available for this variant.
PS3	Not met	No variant-specific functional data or systematic range characterization is available for N439S in ATR. OncoKB reports unknown oncogenic effect with no curated functional evidence. No experimental studies were identified in the literature that directly tested this variant or a systematically characterized range containing it.	oncokb
PS4	Not met	No case-control or cohort prevalence data comparing affected versus unaffected individuals is available for this variant.
PS5	Not met	No reputable source has reported this variant as pathogenic. The variant is absent from ClinVar and the literature.	clinvar
PM1	Not met	The N439 residue does not lie in a statistically significant hotspot on cancerhotspots.org, and no functional domain characterization was identified in the available evidence that specifically defines N439 as situated within a well-characterized critical functional domain.
PM2	Met	This variant is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes). Allele frequency is 0 in all population databases, meeting the PM2 threshold of <0.1%.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not met	No different pathogenic missense variant at the same amino acid residue (N439) has been identified. PM5 candidate harvesting found no comparator variants at this residue in ClinVar.	pm5_candidates clinvar
PM6	Not met	No de novo occurrence data with confirmed maternity and paternity testing is available for this variant.
PP1	Not met	No segregation data is available for this variant in affected families.
PP2	Not met	No HCI missense constraint prior data is available for this gene-variant pair, and no gene-level missense constraint (Z-score) data was retrieved. Insufficient evidence to apply PP2.
PP3	Not met	In silico tools do not support a deleterious prediction. REVEL score is 0.042 (well below clinical pathogenic threshold), BayesDel score is -0.769573 (benign range), and SpliceAI max delta is 0.02 (no predicted splice alteration). All available tools point toward a benign effect.	revel bayesdel spliceai
PP4	Not met	No phenotype specificity data is available. The variant has not been reported in clinically characterized patients to allow assessment of phenotypic specificity.
PP5	Not met	No reputable source has reported this variant as pathogenic. The variant has no ClinVar entries and is not cited in the literature.	clinvar
BA1	Not met	This variant is absent from all population databases (gnomAD v2.1, v4.1, and gnomAD-Canada). It does not meet the BA1 threshold of allele frequency >1%.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	This variant is absent from all population databases. It does not meet the BS1 threshold of allele frequency >0.3%.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	No data on observation of this variant in healthy adult individuals is available. The variant is absent from gnomAD, precluding assessment of homozygous or high-frequency observations in controls.
BS3	Not met	No functional studies demonstrating a neutral or benign effect on protein function are available for N439S in ATR.	oncokb
BS4	Not met	No segregation data is available to demonstrate lack of cosegregation with disease in affected families.
BP1	Not met	Although ATR loss-of-function is supported as a germline disease mechanism by targeted literature review, there is insufficient evidence to establish that truncating variants are the only or primary mechanism of ATR-related disease. The available gene-level literature does not support restricting pathogenesis solely to truncating variants.	pvs1_gene_context
BP2	Not met	No observations of this variant in trans with a known pathogenic ATR variant are available.
BP3	N/A	Trivially not applicable: this is a missense substitution, not an in-frame indel in a repetitive region.
BP4	Met	Multiple in silico tools predict no significant impact on protein function or splicing. REVEL score is 0.042 (well below clinical pathogenic threshold), BayesDel score is -0.769573 (benign range), and SpliceAI max delta score is 0.02 (no predicted splice alteration at canonical sites). All available computational evidence supports a benign effect.	revel bayesdel spliceai
BP5	Not met	No case in which an alternative molecular basis for disease was identified while this variant was also present is available.
BP6	Not met	No reputable source has reported this variant as benign. The variant has no ClinVar entries.	clinvar
BP7	N/A	This is a missense variant (c.1316A>G, p.Asn439Ser). BP7 applies only to synonymous/silent variants with no predicted splice impact. Not applicable to missense substitutions.
PM3	N/A	Trivially not applicable: no variant-specific data for recessive/trans configuration assessment is available.
PM4	N/A	Trivially not applicable: this is a missense substitution, not a non-frameshift indel or stop-loss variant.

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