NM_001184.3:c.2112G>T

ATR · NP_001175.2:p.(Lys704Asn) · NM_001184.3

GRCh37: chr3:142274948 C>A · GRCh38: chr3:142556106 C>A

Gene: ATR Transcript: NM_001184.3

Final call

VUS

PM2 moderate BP4 supporting

Variant details

Gene

ATR

Transcript

NM_001184.3

Protein

NP_001175.2:p.(Lys704Asn)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_001184.3:c.2112G>T (p.Lys704Asn) in ATR is a missense variant absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases (PM2_moderate).

Multiple in silico predictors support a benign effect: REVEL score 0.15, BayesDel score -0.360, and SpliceAI max delta 0.16 indicate no significant impact on protein function or splicing (BP4_supporting).

This variant is absent from ClinVar with no functional studies, segregation data, de novo reports, or case-control evidence available. The evidence profile consists of one pathogenic moderate criterion (PM2) and one benign supporting criterion (BP4), resulting in a classification of Uncertain Significance under the generic ACMG/AMP 2015 framework (PMID:25741868).

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	Missense variant (p.Lys704Asn); PVS1 is reserved for null variants (nonsense, frameshift, canonical ±1,2 splice consensus) under the generic ClinGen SVI PVS1 framework (PMC6185798). This variant does not fall into any null-variant bucket.	pvs1_variant_assessment pvs1_generic_framework
PS1	Not met	No alternate nucleotide change at the same position (c.2112) resulting in the same amino acid substitution (Lys704Asn) has been identified as pathogenic in ClinVar or the literature.	clinvar pm5_candidates
PS2	Not met	No de novo data available for this variant. No publications or databases report this variant as de novo.
PS3	Not met	No functional studies have been identified for NM_001184.3:c.2112G>T (p.Lys704Asn) or a systematically characterized range that includes this position. OncoKB reports unknown oncogenic effect with no variant-specific reviewed functional evidence.	oncokb
PS4	Not met	No case-control or cohort enrichment data available for this variant. The variant is absent from ClinVar and not reported in any publication.	clinvar
PS5	N/A	PS5 is not a standard ACMG/AMP 2015 criterion. This code is not defined in the Richards et al. (PMID:25741868) framework or the ClinGen SVI recommendations.	generic_acmg_combination_rules
PM1	Not met	Position 704 does not fall within a statistically significant mutational hotspot (cancerhotspots.org negative) and no evidence was identified characterizing this residue as part of a critical functional domain with established pathogenic enrichment. ATR is a large multi-domain protein; domain-level attribution requires published characterization data not available for this position.
PM2	Met	This variant is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes), meeting the PM2 threshold of allele frequency < 0.1% in all population databases under the generic ACMG/AMP framework.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not met	No pathogenic missense variant at the same residue (Lys704) has been identified in ClinVar. Automated PM5 candidate search yielded zero same-residue comparator variants.	pm5_candidates clinvar
PM6	Not met	No de novo data available for this variant. No publications report NM_001184.3:c.2112G>T as a de novo occurrence.
PP1	Not met	No cosegregation data available for this variant. No family studies or linkage data have been reported.
PP2	Not met	No evidence was provided in the evidence brief demonstrating that ATR has a low rate of benign missense variation (e.g., missense Z-score, missense constraint metrics). Without explicit constraint data, PP2 cannot be applied.
PP3	Not met	Multiple lines of computational evidence do not support a deleterious effect. REVEL score is 0.15 (below 0.5 threshold), BayesDel score is -0.360 (below pathogenic threshold), and SpliceAI max delta score is 0.16 (no significant splice impact). All in silico predictors favor a benign interpretation.	revel bayesdel spliceai
PP4	Not met	No patient phenotype or family history data are available for assessment. PP4 requires a phenotype highly specific for a disease with a single genetic etiology, which cannot be evaluated without clinical data.
PP5	Not met	This variant is absent from ClinVar. No reputable source (expert panel or clinical laboratory) has classified it as pathogenic. Under the global PP5 rule, ClinVar 3-star expert panel classification is required for supporting-level application, and no such classification exists.	clinvar
BA1	Not met	This variant is absent from gnomAD population databases. Allele frequency does not exceed the 1% BA1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	This variant is absent from gnomAD population databases. Allele frequency does not exceed the 0.3% BS1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	No data are available regarding observation of this variant in healthy adults with full penetrance expected. The variant is absent from population databases but observation in known healthy adult carriers would require individual-level phenotype data not present.
BS3	Not met	No in vitro or in vivo functional studies have been identified that demonstrate no damaging effect for NM_001184.3:c.2112G>T (p.Lys704Asn). OncoKB reports unknown oncogenic effect with no variant-specific functional evidence.	oncokb
BS4	Not met	No segregation data are available to assess lack of segregation with disease in affected family members.
BP1	Not met	No evidence demonstrates that ATR is a gene for which primarily truncating variants cause disease and missense variants are benign. While loss of function is supported as a disease mechanism in ATR, explicit evidence that missense variants are not pathogenic is absent.	pvs1_gene_context
BP2	Not met	No phasing data are available. Observation in trans with a pathogenic variant cannot be assessed without individual-level genotyping data.
BP4	Met	Multiple lines of computational evidence suggest no impact on the gene product. REVEL score is 0.15 (consistent with benign), BayesDel score is -0.360 (consistent with benign), and SpliceAI max delta score is 0.16 (no significant splice alteration).	revel bayesdel spliceai
BP5	Not met	No data are available regarding an alternate molecular basis for disease in a case harboring this variant.
BP6	Not met	This variant is absent from ClinVar. No reputable source has classified it as benign. Under the global BP6 rule, ClinVar 3-star expert panel classification is required for supporting-level application, and no such benign classification exists.	clinvar
BP7	N/A	Variant is a missense substitution (c.2112G>T, p.Lys704Asn), not a synonymous/silent variant. BP7 applies only to synonymous variants with no predicted splice impact.	spliceai
BP3	N/A	Variant is a missense substitution, not an in-frame deletion/insertion in a repetitive region.
PM3	N/A	No phasing or trans-configuration data available for recessive disorders.
PM4	N/A	Variant is a substitution, not an in-frame deletion/insertion or stop-loss variant.

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