Submissions for variant NM_000051.4(ATM):c.1A>G (p.Met1Val)

dbSNP: rs730881359

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000258119	SCV000678094	likely pathogenic	Ataxia-telangiectasia syndrome	2016-11-29	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001093019	SCV001249794	likely pathogenic	not provided	2019-10-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001175687	SCV001339384	pathogenic	Hereditary cancer-predisposing syndrome	2023-05-22	criteria provided, single submitter	clinical testing	This variant results in the loss of the translation start codon (methionine at codon 1) of the ATM gene. This variant is expected to disrupt the expression of the full-length ATM protein. The next in-frame methionine occurs at codon 94, but it has not been shown if a functional ATM protein product can be produced using p.Met94 as an alternative translation start site. This variant has been reported in trans with p.Gly2891Asp variant in an individual affected with breast cancer and mild ataxia-telangiectasia (PMID: 22146522). Cells derived from this patient showed 10-20% of kinase activity compared to normal cells. A functional study has shown that the cells transfected with this variant construct show a very low level expression of a truncated protein, probably due to the use of a downstream methionine for translation initiation (PMID: 22146522). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different translation initiation codon loss variant (ATM c.2T>C / p.Met1?) is a well documented pathogenic variant (Clinvar variation ID: 187213). Based on the available evidence, this variant is classified as Pathogenic.
Invitae	RCV000258119	SCV001583011	pathogenic	Ataxia-telangiectasia syndrome	2023-12-08	criteria provided, single submitter	clinical testing	This sequence change affects the initiator methionine of the ATM mRNA. The next in-frame methionine is located at codon 94. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individuals with ataxia-telangiectasia (PMID: 9463314, 12552559, 21665257, 21792198, 22146522, 22649200). ClinVar contains an entry for this variant (Variation ID: 181942). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV001175687	SCV002717798	pathogenic	Hereditary cancer-predisposing syndrome	2021-12-09	criteria provided, single submitter	clinical testing	The p.M1? pathogenic mutation (also known as c.1A>G), located in coding exon 1 of the ATM gene, results from a A to G substitution at nucleotide position 1. This alters the methionine residue at the initiation codon (ATG). This alteration and several others affecting the initiation codon in ATM have been reported in individuals with ovarian cancer, breast cancer, and prostate cancer (Crawford B et al. Breast Cancer Res. Treat., 2017 Jun;163:383-390; Carter NJ et al. Gynecol. Oncol., 2018 12;151(3):481-488; Zafeiriou Z et al. Eur. Urol., 2019 01;75(1):184-192; Decker B at al. J. Med. Genet., 2017 11;54(11):732-741). Initiation codon alterations, including this alteration. have also been reported in a compound heterozygous state in multiple patients with ataxia telangiectasia (Gilad S et al. Hum. Mol. Genet., 1996 Apr;5:433-9; Stankovic T et al. Am. J. Hum. Genet., 1998 Feb;62(2):334-45; Buzin CH et al. Hum. Mutat., 2003 Feb;21:123-31; Reiman A et al. Br. J. Cancer, 2011 Aug;105(4):586-91; Byrd PJ et al. Br. J. Cancer, 2012 Jan;106:262-8; Schon et al. Ann. Neurol., 2019 02;85(2):170-180). In addition to the clinical data presented in the literature, sequence variations that modify the initiation codon are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Myriad Genetics, Inc.	RCV003137690	SCV003806505	pathogenic	Familial cancer of breast	2023-02-03	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant is located within the gene translation start codon (p.Met1?) and is predicted to result in abnormal protein translation. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 21665257, 9463314, 21792198, 12552559, 22649200, 22146522, 30549301].
GeneReviews	RCV000258119	SCV000328265	not provided	Ataxia-telangiectasia syndrome		no assertion provided	literature only
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355020	SCV001549777	pathogenic	Familial pancreatic carcinoma		no assertion criteria provided	clinical testing	The ATM c.1A>G variant was identified in the literature however the frequency of this variant in an affected population was not provided. The variant was also identified in dbSNP (ID: rs730881359) as “With Pathogenic, other” allele ,ClinVar (classified as pathogenic by GeneReviews and as likely pathogenic by Counsyl).The variant was not identified in the LOVD 3.0 database. The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.1A>G variant occurs in the first base of the translation initiation site (the methionine amino acid start site), increasing the likelihood this variant may disrupt translation or lead to an abnormal protein product. The variant was observed in a breast cancer patient with severe reaction to radiotherapy who was found to have 2 ATM mutations: c.1A>G and c.8672G>A (Byrd, 2012). The mutations were found to be on different alleles, and the c.8762G>A allele's resulting mutant protein was expressed and shown to have some residual ATM kinase activity in lymphoblastoid and skin fibroblast cell lines. The c.1A>G variant was hypothesized to ablate the initiation of ATM protein translation entirely but the possibility of the expression of ATM protein if the GUG of the RNA were able to allow translation could not be ruled out. The possibility that initiation from a downstream methionine resulting in a truncated protein was also considered. The c.1A>G mutation was modelled individually by site-directed mutagenesis of full-length normal ATM cDNA. Very low protein levels were observed and the molecular weight was lower that wild type protein, and the kinase level or the resulting protein was too low to be measured in this assay. These observations were consistent with a second patient with a different mutation of the initiation codon. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.