ATM

Final classification

Benign

ATM c.2873A>G · p.Glu958Gly

ATM

Gene

ATM

Transcript

NM_000051.4

HGVS · transcript:coding

NM_000051.4:c.2873A>G

Consequence

N/A

GRCh38

chr11:108271098 A>G

GRCh37

chr11:108141825 A>G

Basis Richards et.al., 2015 - Combining rules v1.5.0 criteria-combination framework: matched Rule16 (Benign.Strong >=2) with applied criteria: BS1 strong, BS3 moderate, BP2 strong, BP4 supporting; maps to Benign. ▾

Richards et.al., 2015 - Combining rules v1.5.0 criteria-combination framework: matched Rule16 (Benign.Strong >=2) with applied criteria: BS1 strong, BS3 moderate, BP2 strong, BP4 supporting; maps to Benign.

Classification rationale

BS1BS3BP2BP4 Benign

ATM c.2873A>G

BS1_Strong: The variant is present in gnomAD v4.1 at a grpmax filtering allele frequency of 0.0752%, exceeding the ATM VCEP threshold of >0.05% for BS1. The variant has been observed on 90 alleles including one homozygous individual, with highest frequency in the South Asian population (0.091%).¹ BS3_Moderate: Comprehensive functional assessment of all ATM SNVs using prime editing and deep learning (PMID:40580951) classifies p.Glu958Gly as 'Functional' with high confidence. The variant rescues both ATM-specific phosphorylation activity and radiosensitivity, meeting VCEP criteria for BS3_Moderate.² BP2_Strong: c.2873A>G has been observed in cis with a known pathogenic ATM variant (c.5932G>T, p.Glu1978*) on the same allele, corresponding to -4.0 points (BP2_Strong) under the ATM VCEP PM3/BP2 table.³ BP4_Supporting: REVEL score of 0.121 is below the VCEP benign threshold of ≤0.249. BayesDel score of -0.224 is consistent with a benign prediction. SpliceAI predicts no significant splice impact (max delta 0.19).⁴ No pathogenic criteria were met: PVS1 is not applicable (missense variant). PS1 is not met (no same amino acid change classified as pathogenic at codon 958). PS3 is not met (functional studies show normal, not damaging, effect). PM2 is not met (AF=0.00558% exceeds ≤0.001% VCEP threshold). PP3 is not met (REVEL=0.121 below >0.7333 threshold; SpliceAI=0.19 below ≥0.2 threshold).⁵

BS1 + BS3 + BP2 + BP4 → Benign

1 gnomad_v4 ↗

2 PMID:40580951 ↗vcep_suppl_tables1_pmid_40580951

3 vcep_atm_pm3_bp2_1_5

4 revelbayesdelspliceai ↗

5 revelspliceai ↗gnomad_v4 ↗vcep_suppl_tables1_pmid_40580951

Gene diagram · NM_000051.4 · variants mapped to exon structure

ATM NM_000051.4

Fetching transcript structure from UCSC…

Applied criteria · 4 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

Benign evidence

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

Research & evidence

Population frequency · supports benign

gnomAD v4.1

gnomAD v2.1

Population frequency

homozygote observed in gnomAD v4.1. Healthy biallelic carriers are difficult to reconcile with a fully penetrant loss-of-function disease allele.

Overall AF

90 / 1,614,012

0.0056%

Highest · South Asian

0.091%

Homozygotes

grpmax FAF

0.075%

Allele frequency by ancestry — gnomAD v4.1

observed in 4 of 9 groups

Ancestry	Allele count	Frequency	Homozygotes
South Asian	83 / 91,088	0.091%	1
Admixed American	1 / 59,996	0.0017%	0
African/African American	1 / 74,918	0.0013%	0
European (non-Finnish)	2 / 1,180,036	0.00017%	0
European (Finnish)	0 / 64,002	—	—
Amish	0 / 912	—	—
East Asian	0 / 44,884	—	—
Middle Eastern	0 / 6,084	—	—
Ashkenazi Jewish	0 / 29,604	—	—

“

This variant is present in gnomAD v4.1 (AF= 5.57617e-05; MAF= 0.00558%, 90/1614012 alleles, homozygotes = 1) and has highest observed frequency in the South Asian population (AF= 0.000911207; MAF= 0.09112%, 83/91088 alleles, homozygotes = 1); grpmax FAF= 0.00075231.

Overall AF

24 / 251,422

0.0095%

Highest · South Asian

0.072%

Homozygotes

grpmax FAF

0.049%

Allele frequency by ancestry — gnomAD v2.1

observed in 3 of 8 groups

Ancestry	Allele count	Frequency	Homozygotes
South Asian	22 / 30,612	0.072%	0
Admixed American	1 / 34,590	0.0029%	0
European (non-Finnish)	1 / 113,732	0.00088%	0
African/African American	0 / 16,248	—	—
Ashkenazi Jewish	0 / 10,078	—	—
East Asian	0 / 18,390	—	—
European (Finnish)	0 / 21,638	—	—
Remaining individuals	0 / 6,134	—	—

“

This variant is present in gnomAD v2.1 (AF= 9.5457e-05; MAF= 0.00955%, 24/251422 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.000718672; MAF= 0.07187%, 22/30612 alleles, homozygotes = 0); grpmax FAF= 0.00048585.

“

This variant is absent from gnomAD-Canada.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Uncertain significance (6 clinical laboratories) and as Likely benign (3 clinical laboratories). (ClinVarID = 133611)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.19). REVEL score = 0.121. BayesDel score = -0.224243.

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. ATM, a kinase involved in the DNA damage response, is mutated in various solid and hematologic malignancies.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

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

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Literature · 17 PMIDs triaged · 8 high-priority

17papers screened

Papers triaged by theme: functional/splicing/segregation/case_observation. high_priority_papers include abstract snippets. Use these to support PS3/BS3/PS4/PP1/PP3/PP5.

25741868 ↗ functional

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

The American College of Medical Genetics and Genomics (ACMG) previously developed guidance for the interpretation of sequence variants.(1) In the past decade, sequencing technology has evolved rapidly with the advent of high-throughput next-generation sequencing. By adopting and leveraging next-generation sequencing, clinical laboratories are now performing an ever-increasing catalogue of genetic

BS3PP5PS3PS4

40580951 ↗ functional

Functional assessment of all ATM SNVs using prime editing and deep learning.

Ataxia telangiectasia mutated (ATM), a large gene with 63 exons, plays a critical role in the DNA damage response, and its loss of function increases cancer risk and affects the prognosis of cancer patients. However, interpreting the functional impact of ATM variants remains challenging because most are variants of uncertain significance (VUSs). Here, we assessed the functions of all 27,513 possib

BS3PP5PS3PS4

20301317 ↗ case observation

Untitled reference

PP5PS4

20301790 ↗ case observation

Untitled reference

PP5PS4

24418350 ↗ case observation

EFNS/ENS Consensus on the diagnosis and management of chronic ataxias in adulthood.

The ataxias are a challenging group of neurological diseases due the aetiological heterogeneity and the complexity of the genetic subtypes. This guideline focuses on the heredodegenerative ataxias. The aim is to provide a peer-reviewed evidence-based guideline for clinical neurologists and other specialist physicians responsible for the care of patients with ataxia. This guideline is based on syst

PP5PS4

24728327 ↗ case observation

Germline variation in cancer-susceptibility genes in a healthy, ancestrally diverse cohort: implications for individual genome sequencing.

Technological advances coupled with decreasing costs are bringing whole genome and whole exome sequencing closer to routine clinical use. One of the hurdles to clinical implementation is the high number of variants of unknown significance. For cancer-susceptibility genes, the difficulty in interpreting the clinical relevance of the genomic variants is compounded by the fact that most of what is kn

PP5PS4

25394175 ↗ case observation

A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.

The practice guidelines of the American College of Medical Genetics and Genomics (ACMG) and the National Society of Genetic Counselors (NSGC) are developed by members of the ACMG and NSGC to assist medical geneticists, genetic counselors, and other health-care providers in making decisions about appropriate management of genetic concerns, including access to and/or delivery of services. Each pract

PP5PS4

26389210 ↗ case observation

Untitled reference

PP5PS4

20050888 ↗ background review

EFNS guidelines on the molecular diagnosis of ataxias and spastic paraplegias.

PP5PS4

28492532 ↗ background review

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

PP5PS4

Sources & reference links

8Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots