Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_000051.4(ATM):c.6976-2A>C

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA294376

142355 (ClinVar)

Gene: ATM

Condition: ATM-related cancer predisposition

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: b1e30296-5bb3-4da2-b606-eff8628b5902

Approved on: 2024-11-26

Published on: 2025-01-13

HGVS expressions

NM_000051.4:c.6976-2A>C

NM_000051.4(ATM):c.6976-2A>C

NC_000011.10:g.108327643A>C

CM000673.2:g.108327643A>C

NC_000011.9:g.108198370A>C

CM000673.1:g.108198370A>C

NC_000011.8:g.107703580A>C

NG_009830.1:g.109812A>C

NG_054724.1:g.147190T>G

ENST00000452508.7:c.6976-2A>C

ENST00000713593.1:c.*6447-2A>C

ENST00000278616.9:c.6976-2A>C

ENST00000525056.2:n.1395-2A>C

ENST00000682286.1:n.1733-2A>C

ENST00000682302.1:n.1394-2A>C

ENST00000683174.1:n.8460-2A>C

ENST00000683524.1:n.2200-2A>C

ENST00000684152.1:n.2690-2A>C

ENST00000684447.1:n.1437A>C

ENST00000527805.6:c.*2040-2A>C

ENST00000675595.1:c.*2111-2A>C

ENST00000675843.1:c.6976-2A>C

ENST00000278616.8:c.6976-2A>C

ENST00000452508.6:c.6976-2A>C

ENST00000524792.5:n.3191-2A>C

ENST00000525537.2:n.250A>C

ENST00000525729.5:c.641-18572T>G

ENST00000533690.5:n.2380-2A>C

NM_000051.3:c.6976-2A>C

NM_001330368.1:c.641-18572T>G

NM_001351110.1:c.*38+7577T>G

NM_001351834.1:c.6976-2A>C

NM_001330368.2:c.641-18572T>G

NM_001351110.2:c.*38+7577T>G

NM_001351834.2:c.6976-2A>C

Pathogenic

PM2_Supporting PVS1 PM3_Supporting

PM5

Evidence Links 0

Expert Panel

Hereditary Breast, Ovarian and Pancreatic Cancer VCEP

Criteria Specification Information

Criteria Specification: ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for ATM Version 1.3.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Hereditary Breast, Ovarian and Pancreatic Cancer VCEP

The c.6976-2A>C variant in ATM occurs within the canonical splice acceptor site (+/- 1,2) of intron 47. It is predicted to cause skipping of a biologically-relevant-exon, resulting in an in-frame deletion that is predicted to escape nonsense mediated decay. This prediction is confirmed by RNA analysis (PMID: 31843900; Ambry internal data). This variant has been detected in at least 1 individual with Ataxia-Telangiectasia (PMID: 26896183). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0000088 in the European (non-Finnish) population, which is lower than the ClinGen HBOP threshold (≤.00001) for PM2_Supporting, meeting this criterion. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant ATM-related cancer predisposition and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied, as specified by the HBOP Variant Curation Expert Panel. (PVS1(RNA), PM3_Supporting, PM2_Supporting)

PM2_Supporting

The highest population minor allele frequency in gnomAD v2.1.1 is 0.001% in European (non-Finnish) population, which is lower than the ClinGen HBOP threshold (</=0.001%) for PM2_Supporting, meeting this criterion.

PVS1

Demonstrated to cause aberrant splicing, resulting in skipping of biologically-relevant-exon 48, in a gene in which loss-of-function is an established disease mechanism (PMID: 31843900; Ambry internal data) PVS1 (RNA).

PM3_Supporting

This variant has been detected in 1 individual with ataxia-telangiectasia (PMID:26896183, PM3_Supporting).

PM5

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

Curation History

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.