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.1844T>C (p.Leu615Pro)

CA197807

187501 (ClinVar)

Gene: ATM (HGNC:472)

Condition: ATM-related cancer predisposition (MONDO:0700270)

Inheritance Mode: Autosomal dominant inheritance

UUID: 818bf464-ba1b-47c5-946b-f1ab49ee4823

Approved on: 2025-11-11

Published on: 2026-04-10

HGVS expressions

NM_000051.4:c.1844T>C

NM_000051.4(ATM):c.1844T>C (p.Leu615Pro)

NC_000011.10:g.108252858T>C

CM000673.2:g.108252858T>C

NC_000011.9:g.108123585T>C

CM000673.1:g.108123585T>C

NC_000011.8:g.107628795T>C

NG_009830.1:g.35027T>C

ENST00000452508.7:c.1844T>C

ENST00000713593.1:c.*1315T>C

ENST00000278616.9:c.1844T>C

ENST00000682516.1:n.1978T>C

ENST00000683174.1:n.1994T>C

ENST00000683605.1:n.1339T>C

ENST00000684037.1:c.*779T>C

ENST00000684061.1:n.1978T>C

ENST00000527805.6:c.1844T>C

ENST00000675595.1:c.1679T>C

ENST00000675843.1:c.1844T>C

ENST00000278616.8:c.1844T>C

ENST00000452508.6:c.1844T>C

ENST00000525012.5:n.38T>C

ENST00000527805.5:c.1844T>C

ENST00000533526.1:n.38T>C

NM_000051.3:c.1844T>C

NM_001351834.1:c.1844T>C

NM_001351834.2:c.1844T>C

Likely Pathogenic

PM3_Strong PP3 PM2_Supporting

PS3 PS4 PS2 PS1 PP4 PP1 PP2 BA1 PM1 PM4 PM5 BS2 PM6 BS3 BS4 BS1 BP2 BP3 BP4 BP1 BP5 BP7 PVS1

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 1.4.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Hereditary Breast, Ovarian and Pancreatic Cancer VCEP

The c.1844T>C variant in ATM is a missense variant predicted to cause substitution of leucine by proline at amino acid 615 (p.Leu615Pro). This variant has been detected in at least three unrelated individuals with Ataxia-Telangiectasia (PMID: 30549301, 32901917, external communication with Labcorp Genetics (formerly Invitae)). The highest population minor allele frequency in gnomAD v4.1.0 is 0.000003392 in the European (non-Finnish) population, which is lower than the HBOP VCEP threshold (≤0.00001) for PM2_Supporting, and therefore meets this criterion. The computational predictor REVEL gives a score of 0.792, which is above the threshold of 0.7333, evidence that correlates with impact to ATM function. In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant ATM-related cancer predisposition and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied as specified by the HBOP VCEP. (PM3_Strong, PM2_Supporting, PP3)

PM3_Strong

This variant has been detected in at least 3 individuals with Ataxia Telangiectasia. Of these individuals, two are compound heterozygous with P/LP variants, with one confirmed to be in trans (PMID: 30549301, Invitae patient). (6 points). The third individual is a compound heterozygote with the second variant, c.8687A>C, confirmed to be in trans but classified as a VUS (PMID: 32901917) (0.5 points). Total 6.5 points - (PM3_strong)

PP3

The computational predictor REVEL gives a score of 0.792, which is above the threshold of 0.7333, evidence that correlates with impact to ATM function (PP3).

PM2_Supporting

The highest population minor allele frequency in gnomAD v4.1.0 is 0.000003392 (4/1179414 alleles) in European (non-Finnish) population, which is lower than the ClinGen HBOP threshold (<0.00001) for PM2_Supporting, meeting this criterion (PM2_Supporting).

PS3

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

PS4

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

PS2

not applicable

PS1

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

PP4

Ataxia patients counted under PM3

PP1

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

PP2

not applicable

BA1

Present at a low frequency in gnomADv4

PM1

not applicable

PM4

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

PM5

4 different missense variants, (c.1843C>T, p.Leu615Phe,c.1843C>G, c.1843C>G, p.Leu615Val, c.1844T>G p.Leu615Arg, c.1844T>A, p.Leu615His), in the same codon have been reported in patients with breast cancer or ataxia telangiectasia. However, these variants have not yet met the criteria to be classified as pathogenic or likely pathogenic by the ClinGen HBOP.

BS2

not applicable

PM6

not applicable

BS3

No functional studies available

BS4

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

BS1

Present at a low frequency in gnomADv4 which is below the threshold of 0.05%.

BP2

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

BP3

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

BP1

not applicable

BP5

not applicable

BP7

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

PVS1

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

Curation History

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