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).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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