Starting

Initialising…

ATM

Final classification

Uncertain Significance - Conflicting Evidence

ATM c.6801C>T · p.Asn2267=

ATM

The ATM c.6801C>T (p.Asn2267=; p.N2267=) variant has been reported in ClinVar as likely benign or benign by three clinical laboratory submissions.

Gene

ATM

Transcript

NM_000051.4

HGVS · transcript:coding

NM_000051.4:c.6801C>T

Consequence

N/A

GRCh38

chr11:108325538 C>T

GRCh37

chr11:108196265 C>T

Basis Richards et.al., 2015 - Combining rules v1.5.0 criteria-combination framework: matched Rule31 (Benign.Supporting >=1 + Pathogenic.Supporting >=1) with applied criteria: PM2 supporting, BP7 supporting; maps to Uncertain Significance - Conflicting Evidence. ▾

Richards et.al., 2015 - Combining rules v1.5.0 criteria-combination framework: matched Rule31 (Benign.Supporting >=1 + Pathogenic.Supporting >=1) with applied criteria: PM2 supporting, BP7 supporting; maps to Uncertain Significance - Conflicting Evidence.

Classification rationale

PM2 BP7 Uncertain Significance - Conflicting Evidence

ATM c.6801C>T

The ATM c.6801C>T (p.Asn2267=; p.N2267=) variant has been reported in ClinVar as likely benign or benign by three clinical laboratory submissions.¹ This variant is absent from gnomAD v2.1 and gnomAD-Canada and is present at very low frequency in gnomAD v4.1 (4/1,598,316 alleles; AF 0.00025%), which meets the ATM VCEP PM2_Supporting rarity threshold.² SpliceAI predicts no significant splice impact for this synonymous variant (max delta score 0.00), supporting BP7 and not supporting PP3.³

PM2 + BP7 → Uncertain Significance - Conflicting Evidence

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗cspec ↗

3 spliceai ↗cspec ↗

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

ATM NM_000051.4

Fetching transcript structure from UCSC…

Applied criteria · 2 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

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 2.50263e-06; MAF= 0.00025%, 4/1598316 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 1.61031e-05; MAF= 0.00161%, 1/62100 alleles, homozygotes = 0); grpmax FAF= 6.8e-07.

v2.1

Absent from gnomAD v2.1.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.00025% · 4 / 1,598,316
0 hom · FAF 6.8e-05%

Remaining individuals 1 / 62,100	0.0016%
European (non-Finnish) 3 / 1,168,036	0.00026%

+ 8 not observed (Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Likely benign (2 clinical laboratories) and as Benign (1 clinical laboratory). (ClinVarID = 1113077)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

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 ↗

Sources & reference links

9Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 10 PMIDs not cited in assessment

34242744 ↗ Customizing local and systemic therapies for women with early breast cancer: the St. Gallen International Consensus Guidelines for treatment of early breast cancer 2021. CLINVAR

15604628 ↗ Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors. CLINVAR

17508274 ↗ Risk assessment and genetic counseling for hereditary breast and ovarian cancer: recommendations of the National Society of Genetic Counselors. CLINVAR

18163131 ↗ The emerging landscape of breast cancer susceptibility. CLINVAR

20301317 ↗ Hereditary Ataxia Overview. CLINVAR

20301425 ↗ BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer. CLINVAR

20301790 ↗ Ataxia-Telangiectasia. CLINVAR

24366376 ↗ Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer in women: U.S. Preventive Services Task Force recommendation statement. CLINVAR

20050888 ↗ EFNS guidelines on the molecular diagnosis of ataxias and spastic paraplegias. CLINVAR

28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR