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.8546G>C (p.Arg2849Pro)

CA382518439

490737 (ClinVar)

Gene: ATM (HGNC:472)

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

Inheritance Mode: Autosomal dominant inheritance

UUID: ac4b4286-3493-4bcb-9cea-f24086ea7f27

Approved on: 2022-03-16

Published on: 2025-09-15

HGVS expressions

NM_000051.3:c.8546G>C

NM_000051.3(ATM):c.8546G>C (p.Arg2849Pro)

NC_000011.10:g.108345870G>C

CM000673.2:g.108345870G>C

NC_000011.9:g.108216597G>C

CM000673.1:g.108216597G>C

NC_000011.8:g.107721807G>C

NG_009830.1:g.128039G>C

NG_054724.1:g.128963C>G

ENST00000452508.7:c.8546G>C

ENST00000713593.1:c.*8017G>C

ENST00000278616.9:c.8546G>C

ENST00000638786.2:n.1244G>C

ENST00000682286.1:n.3303G>C

ENST00000682302.1:n.2964G>C

ENST00000683174.1:n.10030G>C

ENST00000683524.1:n.3770G>C

ENST00000684152.1:n.3962G>C

ENST00000684180.1:n.1020G>C

ENST00000684447.1:n.5039G>C

ENST00000527805.6:c.*3610G>C

ENST00000675595.1:c.*3681G>C

ENST00000675843.1:c.8546G>C

ENST00000278616.8:c.8546G>C

ENST00000452508.6:c.8546G>C

ENST00000524755.5:c.227-10578C>G

ENST00000524792.5:n.4761G>C

ENST00000525729.5:c.641-36799C>G

ENST00000526725.1:n.272-5506C>G

ENST00000527531.5:c.*1196+9045C>G

ENST00000615746.4:c.*1196+9045C>G

NM_001330368.1:c.641-36799C>G

NM_001351110.1:c.695-10578C>G

NM_001351834.1:c.8546G>C

NR_147053.2:n.2301+9045C>G

NM_001330368.2:c.641-36799C>G

NM_001351110.2:c.695-10578C>G

NM_001351834.2:c.8546G>C

NM_000051.4:c.8546G>C

NR_147053.3:n.2299+9045C>G

Likely Pathogenic

PS3_Moderate PM2_Supporting PP3 PM3

BA1 BS1 BP4

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 ATM c.8546G>C (p.Arg2849Pro) variant has been observed in a compound heterozygous state (presumed) in an individual with biallelic disease and in heterozygosity in an individual with biallelic disease with a second variant unidentified (PM3, PMID: 23667852, PMID: 9887333). This variant is non-functional in multiple different protein assays (PS3_Moderate, PMID: 11805335). In silico protein predictors (ALIGN GVGD: Class C65; REVEL: 0.919; SIFT: damaging; PolyPhen2: probably damaging) predict that this alteration is deleterious (PP3). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely pathogenic based on the ACMG/AMP criteria applied as specified by the HBOP Variant Curation Expert Panel.

PS3_Moderate

This variant is non-functional in multiple different protein assays. Transfection of ATM cDNA carrying this variant into AT1ABR (ATM-null) cells failed to elicit ATM kinase activity (measured by p53 substrate in vitro phosphorylation and p53 Ser-15 in vivo phosphorylation) and failed to correct radiosensitivity (PMID: 11805335) (PS3_Moderate).

PM2_Supporting

This variant is absent in gnomAD v2.1.1 (PM2_Supporting).

PP3

In silico protein predictors (ALIGN GVGD: Class C65; REVEL: 0.919; SIFT: damaging; PolyPhen2: probably damaging) predict that this alteration is deleterious (PP3). In silico splicing predictors (SpliceAI: AL 0.00/DL 0.01/AG 0.00/DG 0.00; MaxEntScan: 0.00% (wild type = 3.39, variant = 3.39)) find that this variant is unlikely to affect splicing.

PM3

This variant has been observed in a compound heterozygous state (presumed) in an individual with biallelic disease and in heterozygosity in an individual with biallelic disease with a second variant unidentified (PM3, PMID: 23667852, PMID: 9887333).

BA1

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

BS1

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

Curation History

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