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.4394T>C (p.Leu1465Pro)

CA298357

181996 (ClinVar)

Gene: ATM
Condition: hereditary breast cancer
Inheritance Mode: Autosomal dominant inheritance
UUID: afccc577-2d42-4940-8bb7-bbf0b5ea06e3
Approved on: 2024-01-25
Published on: 2024-02-14

HGVS expressions

NM_000051.4:c.4394T>C
NM_000051.4(ATM):c.4394T>C (p.Leu1465Pro)
NC_000011.10:g.108289759T>C
CM000673.2:g.108289759T>C
NC_000011.9:g.108160486T>C
CM000673.1:g.108160486T>C
NC_000011.8:g.107665696T>C
NG_009830.1:g.71928T>C
ENST00000452508.7:c.4394T>C
ENST00000713593.1:c.*3865T>C
ENST00000278616.9:c.4394T>C
ENST00000533733.6:n.1657T>C
ENST00000683174.1:n.4544T>C
ENST00000527805.6:c.4394T>C
ENST00000675595.1:c.4229T>C
ENST00000675843.1:c.4394T>C
ENST00000278616.8:c.4394T>C
ENST00000452508.6:c.4394T>C
ENST00000524792.5:n.609T>C
ENST00000531525.2:c.401T>C
ENST00000533733.5:n.823T>C
NM_000051.3:c.4394T>C
NM_001351834.1:c.4394T>C
NM_001351834.2:c.4394T>C
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Likely Pathogenic

Met criteria codes 3
PP3 PM2_Supporting PM3_Strong
Not Met criteria codes 1
PS3

Evidence Links 0

Expert Panel

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.4394T>C variant in ATM is a missense variant predicted to cause substitution of leucine by proline at amino acid 1465 (p.Leu1465Pro). 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. This variant has been detected in at least one individual with Ataxia-Telangiectasia (PMID 9463314, 10234507, 26896183). The computational predictor, Revel (Score: 0.802), predicts a damaging effect on ATM function. In summary, this variant meets criteria to be classified as likely 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 (PM2_supporting, PM3_strong, PP3).
Met criteria codes
PP3
The computational predictor REVEL gives a score of 0.802, which is above the threshold of ≥.733, evidence that correlates with impact to ATM function. No splicing impact per Splice AI
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.
PM3_Strong
This variant has been detected in an individual with Ataxia-Telangiectasia in the compound heterozygous state with a pathogenic variant (c.1355del) confirmed in trans by parental testing (4 points: PMID 9463314, 10234507, 26896183).
Not Met criteria codes
PS3
No rescue studies, therefore, PS3 is not met according to HBOP VCEP rules.
Curation History
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