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.5236G>A (p.Gly1746Arg)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA16613442

407510 (ClinVar)

Gene: ATM

Condition: hereditary breast cancer

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 4f737153-e8dd-4e1e-9a3f-07bad4253908

Approved on: 2024-01-25

Published on: 2024-02-14

HGVS expressions

NM_000051.4:c.5236G>A

NM_000051.4(ATM):c.5236G>A (p.Gly1746Arg)

NC_000011.10:g.108301706G>A

CM000673.2:g.108301706G>A

NC_000011.9:g.108172433G>A

CM000673.1:g.108172433G>A

NC_000011.8:g.107677643G>A

NG_009830.1:g.83875G>A

ENST00000452508.7:c.5236G>A

ENST00000713593.1:c.*4707G>A

ENST00000278616.9:c.5236G>A

ENST00000683174.1:n.6720G>A

ENST00000683524.1:n.460G>A

ENST00000684152.1:n.950G>A

ENST00000527805.6:c.*300G>A

ENST00000675595.1:c.*300G>A

ENST00000675843.1:c.5236G>A

ENST00000278616.8:c.5236G>A

ENST00000452508.6:c.5236G>A

ENST00000524792.5:n.1451G>A

ENST00000533690.5:n.640G>A

ENST00000534625.1:n.465G>A

NM_000051.3:c.5236G>A

NM_001351834.1:c.5236G>A

NM_001351834.2:c.5236G>A

Pathogenic

PM5_Supporting PM2_Supporting PM3_Supporting PVS1

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 1.2.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Hereditary Breast, Ovarian and Pancreatic Cancer VCEP

The c.5236G>A (p.Gly1746Arg) variant in ATM has been demonstrated to cause aberrant splicing, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (Ambry internal data). This alteration results in a termination codon upstream of the most C-terminus pathogenic alteration (ATM p.Arg3047*), as classified by the HBOP VCEP, and is expected to be more deleterious. This variant was observed in an individual with Ataxia-Telangiectasia (PMID:26896183), and is absent from gnomAD v2.1.1. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hereditary breast cancer and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP (PVS1(RNA), PM2_Supporting, PM3_Supporting, PM5_Supporting).

PM5_Supporting

This alteration results in a termination codon upstream of the most C-terminal pathogenic alteration (ATM p.Arg3047*), as classified by the HBOP VCEP, and is expected to be more deleterious.

PM2_Supporting

This variant is absent from gnomAD v.2.1.1 (PM2_Supporting).

PM3_Supporting

This variant has been detected in 1 individual with ataxia-telangiectasia (PMID:26896183, PM3_Supoorting).

PVS1

Ambry RNA data: 1 RNA case (Heterozygous) picked up r.5178_5319del142 p.V1727Ffs*2 at 40% PSI . This event is completely absent from our control cohort (n>300). Less than 3% of normal spliced reads came from the variant allele. (PVS1 (RNA))

PP3

N/A - PVS1

Curation History

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