ATM

Inheritance Pattern: AD

Disease ID:MONDO:0008315

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0008840

Submitter: Genomics England PanelApp

Inheritance Pattern: AR

Disease ID:MONDO:0008840

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

Inheritance Pattern: AD

Disease ID:MONDO:0005089

Submitter: Genomics England PanelApp

Inheritance Pattern: AD

Disease ID:MONDO:0004950

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0018630

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0008840

Submitter: ClinGen

Ataxia-telangiectasia (AT) is an autosomal recessive disorder characterized by cerebellar ataxia, scleral, mucosal, and cutaneous telangiectasias, variable T and B cell defects, and a predisposition to malignancy including childhood onset lymphoma. Chromosomal breakage is a feature. AT cells are abnormally sensitive to killing by ionizing radiation (IR), and abnormally resistant to inhibition of DNA synthesis by ionizing radiation. The latter trait had been used to identify distinct complementation groups for AT versus Nijmegen Breakage Syndrome (PMID: 3248383). The ATM protein is a member of the phosphatidylinositol 3-kinase family of proteins that respond to DNA damage by phosphorylating key substrates involved in DNA repair and/or cell cycle control. There is abundant evidence published associating the ATM gene with ataxia telangiectasia, since the gene-disease relationship was first proposed by Savitsky K, et al., 1995 (PMID: 7792600). Multiple case level studies have been performed with AT patients that have variants in the ATM gene, including the reports of founder and recurrent pathogenic variants. Loss of function is the mechanism of disease. A significant amount of case-level data is available; the maximum points for genetic evidence has been reached (12 points). ATM protein expression is undetectable in the majority of AT patient cells as missense variants represent less than 10% of pathogenic variants detected. The established ATM homozygous null mouse models show several of the key phenotypes consistent with ataxia telangiectasia, including decreased mature T cells. This is a split curation as the autosomal recessive inherited disorder has unique clinical features and pattern of inheritance from the autosomal dominant inherited hereditary breast carcinoma which was curated separately (ClinGen: 9908). In summary, ATM is definitively associated with autosomal recessive ataxia telangiectasia. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.

Inheritance Pattern: AR

Disease ID:MONDO:0008840

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0008840

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0016419

Submitter: Natera

Inheritance Pattern: AR

Disease ID:MONDO:0008840

Submitter: Natera

Inheritance Pattern: AR

Disease ID:MONDO:0008840

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0008840

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0008840

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0700270

Submitter: ClinGen

ATM was first reported in relation to autosomal dominant ATM-related cancer predisposition in 1987 (Swift et al., PMID: 3574400). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, and inheritance pattern, or phenotypic variability for the autosomal dominant predisposition to cancer descriptions. Therefore, a susceptibility to a range of hereditary cancers, including breast, ovarian, colorectal, and pancreatic cancers, have been lumped into one disease entity, ATM-related cancer predisposition (MONDO:0700270). The recessive disorder Ataxia telangiectasia (MONDO:0008840) was split and curated separately due phenotype and inheritance pattern differences. Several case-control studies were used as genetic evidence (PMIDs: 31406321, 29478780, 30733081, 33471974, 33471991), including data from the CARRIERS consortium (PMID: 33471974) and the Breast Cancer Association Consortium (PMID: 3347199). These studies consistently provided strong evidence that individuals with heterozygous loss-of-function ATM variants are at moderately increased risk for the listed associated cancers. This is supported by the observation that tumors from these individuals feature biallelic loss-of-function variants (PMID: 29478780). Additional evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be loss of function. This gene-disease relationship is also supported by animal modeling (PMID:12195425) and in vitro functional assays (PMIDs: 17525332, 9733514, 10492163, 10999741, 11805335, 12195425). The experimental work consistently demonstrates that ATM loss-of-function variants disrupt DNA damage response, especially in response to ionizing radiation. The signaling function of ATM has been closely related to the function of other known cancer predisposition genes from the same pathway, including BRCA1 (PMID: 10550055). In summary, there is definitive evidence supporting the relationship between ATM and autosomal dominant ATM-related cancer predisposition. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Hereditary Cancer GCEP on the meeting date November 22, 2024 (SOP Version 11).

Inheritance Pattern: AD

Disease ID:MONDO:0016419

Submitter: Ambry Genetics