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ATRc.2112G>TUncertain significance
Print report
Variant interpretation report

ATR c.2112G>T, p.(Lys704Asn)

NM_001184.3:c.2112G>T NP_001175.2:p.(Lys704Asn) View identifiers
Classification
Uncertain significance

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About ATR

No gene-level summary was recorded for this case.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.
01The reasoning

How it was classified

The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 1 Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Moderate
PM2 · moderate

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.

Benign criteria applied · 1
BP4Supporting
BP4 · supporting

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).

Recorded classification: Uncertain significance

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 moderate, BP4 supporting; combination = 1 moderate + 1 supporting benign, which maps to VUS.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

SpliceAI score
0.160 maximum delta

Recorded SpliceAI maximum delta score: 0.160. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4 → SpliceAI ↗
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
Functional evidence
Statement recorded

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. ATR, a tumor suppressor involved in DNA damage repair, is mutated in various cancer types.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

29 criteria with recorded statuses: 2 met · 21 not met · 0 not assessed · 6 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

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).

Met · 2

PM2 ModerateThis 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. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1: absent (AF null
  • AC null)
  • gnomAD v4.1: absent (AF null
  • gnomAD-Canada v1.0: absent (AF 0.0
  • AC 0)
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BP4 SupportingMultiple 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). Details ▾Hide ▴
Evidence considered
  • REVEL: 0.15 (below 0.5 threshold
  • consistent with benign)
  • BayesDel: -0.360 (below pathogenic threshold
  • SpliceAI: max delta 0.16 (no significant splice alteration)
Sources
revelbayesdelspliceai ↗

Not met · 21 · evaluated, threshold not reached

PS1 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. Details ▾Hide ▴
Evidence considered
  • ClinVar contains no entry for this variant or any alternate nucleotide change at c.2112 resulting in K704N.
Sources
clinvar ↗pm5_candidates
PS2 No de novo data available for this variant. No publications or databases report this variant as de novo. Details ▾Hide ▴
Evidence considered
  • No de novo data identified in any source.
Still missing
  • No family-based sequencing or trio data available.
PS3 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. Details ▾Hide ▴
Evidence considered
  • OncoKB: unknown oncogenic effect
  • no variant-specific functional evidence.
Still missing
  • No experimental functional characterization of this variant or its residue.
Sources
oncokb ↗
PS4 No case-control or cohort enrichment data available for this variant. The variant is absent from ClinVar and not reported in any publication. Details ▾Hide ▴
Evidence considered
  • Absent from ClinVar
  • no case reports or cohort studies identified.
Still missing
  • No case-control or burden testing data available for ATR K704N.
Sources
clinvar ↗
PM1 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. Details ▾Hide ▴
Evidence considered
  • Cancerhotspots.org: no statistically significant hotspot at this residue.
Still missing
  • No domain-specific functional characterization data for ATR residue 704.
PM5 No pathogenic missense variant at the same residue (Lys704) has been identified in ClinVar. Automated PM5 candidate search yielded zero same-residue comparator variants. Details ▾Hide ▴
Evidence considered
  • ClinVar: no entries for any variant at ATR residue 704.
  • PM5 candidate search: 0 same-residue candidates found.
Sources
pm5_candidatesclinvar ↗
PM6 No de novo data available for this variant. No publications report NM_001184.3:c.2112G>T as a de novo occurrence. Details ▾Hide ▴
Evidence considered
  • No de novo data identified in any source.
Still missing
  • No trio sequencing or parental testing data available.
PP1 No cosegregation data available for this variant. No family studies or linkage data have been reported. Details ▾Hide ▴
Evidence considered
  • No cosegregation or family linkage data available.
Still missing
  • No family-based segregation analysis available.
PP2 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. Details ▾Hide ▴
Evidence considered
  • No missense constraint metrics (Z-score
  • LOEUF
  • etc.) provided for ATR.
Still missing
  • Missense constraint data not available in evidence brief.
PP3 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. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.15 (benign-leaning
  • below 0.5 threshold)
  • BayesDel: -0.360 (benign-leaning
  • below pathogenic threshold)
  • SpliceAI: max delta 0.16 (no significant splice alteration)
Sources
revelbayesdelspliceai ↗
PP4 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. Details ▾Hide ▴
Evidence considered
  • No patient phenotype data provided.
Still missing
  • No clinical phenotype or family history available.
PP5 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. Details ▾Hide ▴
Evidence considered
  • ClinVar: no entry for this variant
  • no classification from any submitter.
Sources
clinvar ↗
BA1 This variant is absent from gnomAD population databases. Allele frequency does not exceed the 1% BA1 threshold. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1
  • v4.1
  • and Canada: variant absent
  • AF = 0.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS1 This variant is absent from gnomAD population databases. Allele frequency does not exceed the 0.3% BS1 threshold. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1
  • v4.1
  • and Canada: variant absent
  • AF = 0.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS2 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. Details ▾Hide ▴
Evidence considered
  • No individual-level phenotype data on healthy carriers available.
Still missing
  • No healthy adult carrier data with confirmed phenotype.
BS3 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. Details ▾Hide ▴
Evidence considered
  • OncoKB: unknown oncogenic effect
  • no benign functional data available.
Still missing
  • No experimental functional data assessing benign effect of this variant.
Sources
oncokb ↗
BS4 No segregation data are available to assess lack of segregation with disease in affected family members. Details ▾Hide ▴
Evidence considered
  • No segregation data available.
Still missing
  • No family-based segregation analysis available.
BP1 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. Details ▾Hide ▴
Evidence considered
  • PVS1 gene context confirms LoF mechanism supported but does not establish that truncating variants are the primary pathogenic mechanism to the exclusion of missense.
Still missing
  • No gene-level missense vs. truncating constraint comparison data.
Sources
pvs1_gene_context
BP2 No phasing data are available. Observation in trans with a pathogenic variant cannot be assessed without individual-level genotyping data. Details ▾Hide ▴
Evidence considered
  • No phasing or trans-configuration data available.
Still missing
  • No phased genotype data available.
BP5 No data are available regarding an alternate molecular basis for disease in a case harboring this variant. Details ▾Hide ▴
Evidence considered
  • No alternate molecular basis data available.
Still missing
  • No proband data with alternate molecular diagnosis.
BP6 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. Details ▾Hide ▴
Evidence considered
  • ClinVar: no entry for this variant
  • no benign classification from any submitter.
Sources
clinvar ↗
Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AMissense 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. Details ▾Hide ▴
Evidence considered
  • Variant is a missense substitution
  • not a null variant.
Sources
pvs1_variant_assessmentpvs1_generic_framework ↗
PM3 N/ANo phasing or trans-configuration data available for recessive disorders. Details ▾Hide ▴

No further detail was recorded.

PM4 N/AVariant is a substitution, not an in-frame deletion/insertion or stop-loss variant. Details ▾Hide ▴

No further detail was recorded.

BP3 N/AVariant is a missense substitution, not an in-frame deletion/insertion in a repetitive region. Details ▾Hide ▴

No further detail was recorded.

BP7 N/AVariant 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. Details ▾Hide ▴
Evidence considered
  • Variant is missense
  • not synonymous.
Sources
spliceai ↗
PS5 N/APS5 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. Details ▾Hide ▴
Evidence considered
  • PS5 is not a recognized ACMG/AMP criterion.
Sources
generic_acmg_combination_rules

Identifiers

Gene
ATR
Transcript
NM_001184.3
Coding (HGVS c.)
NM_001184.3:c.2112G>T
Protein (HGVS p.)
NP_001175.2:p.(Lys704Asn)
GRCh38
chr3:142556106 C>A
GRCh37
chr3:142274948 C>A

Gene diagram

Every interpreted variant in ATR, mapped onto the exon structure of NM_001184.3. Select a row to find it on the plot.

ATRNM_001184.3
Fetching transcript structure from UCSC…
gnomAD v4.1 Allele count data not recorded
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat +33 bp
0.090
SpliceAI acceptor gainat -66 bp
0.160
SpliceAI donor lossat +277 bp
0.000
SpliceAI donor gainat +342 bp
0.000
Pangolin splice lossmagnitude shown
-0.110
Pangolin splice gain
0.100

Other predictors

REVEL
0.150
BayesDel
-0.360

How the predictions were used

BP4 SupportingMultiple 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). Details ▾Hide ▴
Evidence considered
  • REVEL: 0.15 (below 0.5 threshold
  • consistent with benign)
  • BayesDel: -0.360 (below pathogenic threshold
  • SpliceAI: max delta 0.16 (no significant splice alteration)
Sources
revelbayesdelspliceai ↗
PP3 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. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.15 (benign-leaning
  • below 0.5 threshold)
  • BayesDel: -0.360 (benign-leaning
  • below pathogenic threshold)
  • SpliceAI: max delta 0.16 (no significant splice alteration)
Sources
revelbayesdelspliceai ↗
BP7 N/AVariant 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. Details ▾Hide ▴
Evidence considered
  • Variant is missense
  • not synonymous.
Sources
spliceai ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.16). REVEL score = 0.15. BayesDel score = -0.360396.

0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 Captured gnomAD v4.1 source record Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.160 Open source ↗
ClinVar Captured ClinVar source record Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant is absent from ClinVar.

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.16). REVEL score = 0.15. BayesDel score = -0.360396.

Functional

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. ATR, a tumor suppressor involved in DNA damage repair, is mutated in various cancer types.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.