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.5290del (p.Leu1764fs)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA286887

127405 (ClinVar)

Gene: ATM

Condition: hereditary breast cancer

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: b6f6a451-09ff-4d53-94fa-85c216c95140

Approved on: 2024-01-25

Published on: 2024-02-14

HGVS expressions

NM_000051.4:c.5290del

NM_000051.4(ATM):c.5290del (p.Leu1764fs)

NC_000011.10:g.108301760del

CM000673.2:g.108301760del

NC_000011.9:g.108172487del

CM000673.1:g.108172487del

NC_000011.8:g.107677697del

NG_009830.1:g.83929del

ENST00000452508.7:c.5290del

ENST00000713593.1:c.*4761del

ENST00000278616.9:c.5290del

ENST00000683174.1:n.6774del

ENST00000683524.1:n.514del

ENST00000684152.1:n.1004del

ENST00000527805.6:c.*354del

ENST00000675595.1:c.*354del

ENST00000675843.1:c.5290del

ENST00000278616.8:c.5290del

ENST00000452508.6:c.5290del

ENST00000524792.5:n.1505del

ENST00000533690.5:n.694del

ENST00000534625.1:n.519del

NM_000051.3:c.5290del

NM_001351834.1:c.5290del

NM_001351834.2:c.5290del

Pathogenic

PVS1 PM5_Supporting PM3_Strong

BS1 PS4 PM2

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

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Hereditary Breast, Ovarian and Pancreatic Cancer VCEP

The c.5290del (p.Leu1764TyrfsTer12) variant in ATM is a frameshift variant predicted to cause a premature stop codon in a biologically-relevant-exon leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. 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 has been detected in at least four individuals with Ataxia-Telangiectasia (PMIDs: 22649200, 10425038, 12552559, 18634022, 15928302, 10330348, 18634022, 26896183). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00001763 in the non-Finnish European population (PM2_Supporting, BS1, and BA1 are not met). 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, PM3_Strong, PM5_Supporting)

PVS1

The c.5290del (p.Leu1764TyrfsTer12) variant in ATM is a frameshift variant in a biologically-relevant-exon predicted to cause a premature stop codon leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1).

PM5_Supporting

In the absence of potential splicing rescue mechanisms in ATM, all PVS1-eligble truncating variants are expected to be pathogenic based on the existence of known pathogenic C-terminal truncations in the last exon (PM5_Supporting)

PM3_Strong

This variant has been detected in at least four individuals with ataxia telangiectasia (PMIDs: 22649200, 10425038, 12552559, 18634022, 15928302, 10330348, 18634022, 26896183. Of those individuals, at least one was compound heterozygous for the variant and a pathogenic variant (c.1561_1562delAG, p.(I522fs*43) and the remaining have not yet been classified or are VUS (c.7638_7646del9, c.3248A>G, c.2125delexon16, 5.0 pts, PMIDs: 18634022, 26896183, PM3_strong).

BS1

The filtering allele frequency (the lower threshold of the 95% CI of 2/113458) of the c.5290del variant in ATM is 0.0002930% for European (non-Finnish) chromosomes by gnomAD v2.1.1, which is lower than the ClinGen HBOP VCEP threshold (>0.05%) for BS1, and therefore does not meet this criterion (BS1 not met).

PS4

Identified in 1/443 breast cancer cases and 0/521 controls, however no statistics performed to evaluate weight.

PM2

The highest population minor allele frequency in gnomAD v2.1.1 0.001763% (2/113458) which exceeds the PM2 threshold of 0.001% (PM2_Supporting not met).

Curation History

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