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_000051.3(ATM):c.8585-2A>C

Curation Version - 1.1
Curation History
JSON LD for Version 1.1

CA16613454

407718 (ClinVar)

Gene: ATM

Condition: hereditary breast cancer

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 0645ee73-e418-4371-b16b-d1d98fa56aa2

Approved on: 2022-03-09

Published on: 2022-07-11

HGVS expressions

NM_000051.3:c.8585-2A>C

NM_000051.3(ATM):c.8585-2A>C

NC_000011.10:g.108347277A>C

CM000673.2:g.108347277A>C

NC_000011.9:g.108218004A>C

CM000673.1:g.108218004A>C

NC_000011.8:g.107723214A>C

NG_009830.1:g.129446A>C

NG_054724.1:g.127556T>G

ENST00000278616.9:c.8585-2A>C

ENST00000638786.2:n.1283-2A>C

ENST00000682286.1:n.3342-2A>C

ENST00000682302.1:n.3003-2A>C

ENST00000683174.1:n.10069-2A>C

ENST00000683524.1:n.3809-2A>C

ENST00000684152.1:n.4001-2A>C

ENST00000684180.1:n.1059-2A>C

ENST00000684447.1:n.5078-2A>C

ENST00000527805.6:c.*3649-2A>C

ENST00000675595.1:c.*3720-2A>C

ENST00000675843.1:c.8585-2A>C

ENST00000278616.8:c.8585-2A>C

ENST00000452508.6:c.8585-2A>C

ENST00000524755.5:n.227-11985T>G

ENST00000524792.5:n.4800-2A>C

ENST00000525178.5:n.73-2A>C

ENST00000525729.5:c.641-38206T>G

ENST00000526725.1:n.272-6913T>G

ENST00000527531.5:c.*1196+7638T>G

ENST00000615746.4:c.*1196+7638T>G

NM_001330368.1:c.641-38206T>G

NM_001351110.1:c.695-11985T>G

NM_001351834.1:c.8585-2A>C

NR_147053.2:n.2301+7638T>G

NM_001330368.2:c.641-38206T>G

NM_001351110.2:c.695-11985T>G

NM_001351834.2:c.8585-2A>C

NM_000051.4:c.8585-2A>C

NR_147053.3:n.2299+7638T>G

NM_000051.4(ATM):c.8585-2A>C

Pathogenic

PM2_Supporting PM3_Strong PVS1

BS1 BP4 BA1 PP3

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 1.1

PDF

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Hereditary Breast, Ovarian and Pancreatic Cancer VCEP

The ATM c.8585-2A>C variant is predicted to result in a truncated protein that disrupts a critical functional domain (PVS1). This variant has been observed in a homozygous and compound heterozygous state (presumed) in multiple individuals with Ataxia-Telangiectasia (PM3_Strong; PMID: 23322442, PMID: 29665859). This variant is absent in the gnomAD v2.1.1 cohort (PM2_Supporting). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the HBOP Variant Curation Expert Panel.

PM2_Supporting

This variant is absent in the gnomAD v2.1.1 cohort (PM2_Supporting).

PM3_Strong

This variant has been observed in a homozygous and compound heterozygous state (presumed) in multiple individuals with Ataxia-Telangiectasia (PM3_Strong; PMID: 23322442, PMID: 29665859).

PVS1

The c.8585-2A>C canonical splice variant is predicted to result in a truncated protein that disrupts a critical functional domain (PVS1).

BS1

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

BP4

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

BA1

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

PP3

In silico predictors (SpliceAI: AL 1.00/DL 0.00/AG 0.48/DG 0.00; MaxEntScan: -79.78% (wild type = 10.09, variant = 2.04)) are in agreement this variant affects splicing. However, PP3 was not applied in combination with PVS1 to avoid double counting of predictive evidence.

Curation History

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