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)

Curation Version - 1.3
Curation History
JSON LD for Version 1.3

CA382518439

490737 (ClinVar)

Gene: ATM

Condition: hereditary breast cancer

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

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

Approved on: 2022-03-16

Published on: 2022-07-12

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

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:n.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

NM_000051.4(ATM):c.8546G>C (p.Arg2849Pro)

Likely Pathogenic

PM2_Supporting PS3_Moderate PP3 PM3

BS1 BP4 BA1

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

PDF

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.

PM2_Supporting

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

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).

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).

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

BA1

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

Curation History

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.