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 applied · 11 assessed

Applied · 2

Strength Supporting Moderate Strong Very strong

✓

PM2 supporting Pathogenic

This variant is absent from gnomAD v2.1 and is present at very low frequency in gnomAD v4.1 (4/1,598,316 alleles; AF 0.00025%), which is below the ATM VCEP PM2 threshold of 0.001%. The highest observed subpopulation count is a single allele in the Remaining individuals population (1/62,100; AF 0.00161%), and the ATM VCEP notes that n=1 in a single subpopulation is sufficiently rare for PM2_Supporting.

Absent from gnomAD v2.1.gnomAD v4.1 total AF 2.5026340223084796e-06 (0.00025%)4/1598316 alleles

cspec ↗gnomad_v2 ↗gnomad_v4 ↗

✓

BP7 supporting Benign

This variant is a synonymous substitution, p.(Asn2267=) / p.(N2267=), and SpliceAI predicts no significant splice impact (max delta score 0.00), supporting BP7 for a silent ATM variant.

Synonymous consequence p.(Asn2267=).SpliceAI DS_AG 0.0DS_AL 0.0

cspec ↗spliceai ↗

Assessed · not applied

Pathogenic

PS1 No evidence was identified that this variant produces the same predicted or observed splice defect as a known pathogenic or likely pathogenic ATM variant, so PS1 is not met.

PS3 No published functional study was identified showing that this variant fails ATM-specific rescue assays, so PS3 was not assessed.

PS4 No case-control data were identified showing enrichment of this variant in affected individuals, so PS4 was not assessed.

PM3 No evidence was identified that this variant has been observed in trans with a pathogenic ATM variant in an individual with ataxia-telangiectasia, so PM3 was not assessed.

PP1 No segregation data were identified for this variant, so PP1 was not assessed.

PP3 SpliceAI predicts no significant splice impact for this variant (max delta score 0.00), which is below the ATM VCEP PP3 splicing threshold of 0.2.

Benign

BA1 The highest observed filtering allele frequency in gnomAD v4.1 is 6.8e-07 (0.000068%), which is far below the ATM VCEP BA1 threshold of greater than 0.5%, so BA1 is not met.

BS1 The highest observed filtering allele frequency in gnomAD v4.1 is 6.8e-07 (0.000068%), which is below the ATM VCEP BS1 threshold of greater than 0.05%, so BS1 is not met.

BS3 No published functional study was identified showing rescue of ATM-specific function or radiosensitivity for this variant, so BS3 was not assessed.

BP2 No evidence was identified that this variant co-occurs in trans with a pathogenic ATM variant in an unaffected individual, so BP2 was not assessed.

BP4 SpliceAI predicts no significant splice impact for this variant (max delta score 0.00), which is below the ATM VCEP BP4 threshold of 0.1, but this silent variant is more specifically addressed by BP7 and BP4 was not counted separately to avoid double counting the same computational evidence.

N/A · 15 PVS1 · PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · PP4 · PP5 · BS2 · BS4 · BP1 · BP3 · BP5 · BP6

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

Re-run this variant?