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.9139C>T (p.Arg3047Ter)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA115937

3029 (ClinVar)

Gene: ATM

Condition: hereditary breast cancer

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 4b6c7f5f-b13d-435d-bba1-0d501ef69489

Approved on: 2022-03-09

Published on: 2022-03-09

HGVS expressions

NM_000051.3:c.9139C>T

NM_000051.3(ATM):c.9139C>T (p.Arg3047Ter)

NC_000011.10:g.108365476C>T

CM000673.2:g.108365476C>T

NC_000011.9:g.108236203C>T

CM000673.1:g.108236203C>T

NC_000011.8:g.107741413C>T

NG_009830.1:g.147645C>T

NG_054724.1:g.109357G>A

ENST00000452508.7:c.9139C>T

ENST00000713593.1:c.*8610C>T

ENST00000278616.9:c.9139C>T

ENST00000638786.2:n.1837C>T

ENST00000682286.1:n.3896C>T

ENST00000682302.1:n.3557C>T

ENST00000682569.1:n.2486C>T

ENST00000683174.1:n.10623C>T

ENST00000683524.1:n.4363C>T

ENST00000684152.1:n.4555C>T

ENST00000684180.1:n.1613C>T

ENST00000684447.1:n.5632C>T

ENST00000527805.6:c.*4203C>T

ENST00000675595.1:c.*4274C>T

ENST00000675843.1:c.9139C>T

ENST00000278616.8:c.9139C>T

ENST00000452508.6:c.9139C>T

ENST00000524755.5:c.226+27732G>A

ENST00000524792.5:n.5354C>T

ENST00000525178.5:n.627C>T

ENST00000525729.5:c.640+20444G>A

ENST00000526725.1:n.272-25112G>A

ENST00000527181.1:n.478C>T

ENST00000527531.5:c.*2-9367G>A

ENST00000615746.4:c.*2-9367G>A

NM_001330368.1:c.640+20444G>A

NM_001351110.1:c.694+20444G>A

NM_001351834.1:c.9139C>T

NR_147053.2:n.1107-9367G>A

NM_001330368.2:c.640+20444G>A

NM_001351110.2:c.694+20444G>A

NM_001351834.2:c.9139C>T

NM_000051.4:c.9139C>T

NR_147053.3:n.1105-9367G>A

Pathogenic

PM3_Very Strong PS3_Supporting PP4 PVS1

PM2 BA1 BS1

Evidence Links 1

Expert Panel

Hereditary Breast, Ovarian and Pancreatic Cancer VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Hereditary Breast, Ovarian and Pancreatic Cancer VCEP

The ATM c.9139C>T (p.Arg3047Ter) variant has a GnomAD (v2.1.1) allele frequency of 0.001768% which is above the PM2 threshold of 0.001% but below the BS1 threshold of 0.05%. This variant is expected to produce an NMD-escaping transcript that adversely affects the critical FATKIN domain (PVS1). This variant has been observed in a compound heterozygous state (confirmed) in multiple individuals with ataxia-telangiectasia (PMIDs: 10980530, 26628246, 19691550, PM3_verystrong). This variant is non-functional in a single ATM-specific protein assay (PMID: 19431188, PS3_supporting). This variant was observed in a patient with ataxia-telangiectasia with trace ATM protein expressed but lacking kinase activity (PMID: 22649200 PP4). 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.

PM3_Very Strong

This variant has been observed in a homozygous and/or compound heterozygous state (presumed and/or confirmed) in multiple individuals with Ataxia-Telangiectasia (PMIDs: 10980530, 26628246, 19691550, PM3) (8-POINTS)

PS3_Supporting

Non-functional in a single ATM-specific protein assay (PMID: 19431188) (PS3_Supporting)

supp fig S1b- c.9139C>T shows ~80% ATM protein levels as compared to WT, but >90% reduction in phosphorylation of ATM serine 1981, p53 serine 15 and SMC1 serine 966 as compared to WT. PubMed:19431188

PP4

This variant was observed in a patient with Ataxia-Telangiectasia with trace ATM protein expressed but lacking kinase activity (PMID: 22649200)

PVS1

This variant is expected to produce an NMD-escaping transcript that adversely affects the critical FATKIN domain (PVS1).

PM2

This variant has a GnomAD (v2.1.1) allele frequency of 0.001768% which is above the PM2 threshold of 0.001% but below the BS1 threshold of 0.05%.

BA1

This variant has a GnomAD (v2.1.1) allele frequency of 0.001768% which is below the BA1 threshold of 0.5%.

BS1

This variant has a GnomAD (v2.1.1) allele frequency of 0.001768% which is below the BS1 threshold of 0.05%.

Curation History

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