Submissions for variant NM_000051.4(ATM):c.1A>C (p.Met1Leu)

dbSNP: rs730881359

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166918	SCV000217737	pathogenic	Hereditary cancer-predisposing syndrome	2022-01-19	criteria provided, single submitter	clinical testing	The p.M1? pathogenic mutation (also known as c.1A>C), located in coding exon 1 of the ATM gene and results from an A to C substitution at nucleotide position 1. This alters the methionine residue at the initiation codon (ATG). This mutation was identified in 1/1207 cases of BRCA1/2-negative French women diagnosed with breast cancer who had a sister with breast cancer and in 0/1199 general population controls (Girard E et al. Int J Cancer. 2019 04;144(8):1962-74). Two other disease-causing mutations at the initiation codon, c.3G>A and c.2T>C, have been reported in a compound heterozygous state in patients with Ataxia Telangectasia (AT) (Gilad S, Hum. Mol. Genet. 1996 Apr; 5(4):433-9. Buzin CH, Hum. Mutat. 2003 Feb; 21(2):123-31). Another alteration at the initiation codon, c.1A>G, has been identified in trans with an additional ATM alteration in a patient with very mild AT symptoms. Functional analysis of the two alterations independently revealed that the c.1A>G allele produced very low protein levels, and the protein that was produced was of a lower molecular weight than wild type ATM suggesting initiation at a downstream methionine resulting in a premature truncation codon (Byrd PJ, Br. J. Cancer 2012 Jan; 106(2):262-8). This amino acid position is highly conserved in available vertebrate species. 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.
Counsyl	RCV000576648	SCV000678178	likely pathogenic	Ataxia-telangiectasia syndrome	2017-01-20	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000576648	SCV000807215	pathogenic	Ataxia-telangiectasia syndrome	2017-09-01	criteria provided, single submitter	clinical testing	This start codon mutation is categorized as deleterious according to ACMG guidelines (PMID:18414213). It was found once in our laboratory in trans with a pathogenic missense mutation in a 3-year-old male with hypotonia, ataxic gait, short stature, dysmorphic features.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000576648	SCV000918503	likely pathogenic	Ataxia-telangiectasia syndrome	2017-10-20	criteria provided, single submitter	clinical testing	Variant summary: The ATM c.1A>C (p.Met1Leu) variant involves the alteration of a conserved nucleotide causing a substitution of initiation codon in exon 2 and is located in the Telomere-length maintenance and DNA damage repair domain (IPR021668) (InterPro). 2/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). Since this variant affects the initiation codon, it is expected to alter the translation of ATM protein. Two other substitution variants in the initiation codon (p.Met1Ile and p.Met1Thr) have been classified as likely pathogenic/pathogenic by our laboratory. This variant is absent in 215414 control chromosomes in gnomAD. One clinical diagnostic laboratory has classified this variant as pathogenic. The variant of interest has not, to our knowledge, been reported in affected individuals via publications; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000576648	SCV000941428	pathogenic	Ataxia-telangiectasia syndrome	2023-12-25	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, 21792198, 22649200). ClinVar contains an entry for this variant (Variation ID: 187213). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000166918	SCV001339383	pathogenic	Hereditary cancer-predisposing syndrome	2023-05-22	criteria provided, single submitter	clinical testing	This variant results in the loss of translation initiation methionine codon 1 of the ATM protein. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been observed in trans with a pathogenic missense mutation in a child affected with hypotonia, ataxic gait, short stature, dysmorphic features (Clinvar variation ID: 187213 and SCV000807215.1) and in an individual affected with early-onset breast cancer (Color internal data). 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.
Myriad Genetics, Inc.	RCV004019993	SCV004933103	pathogenic	Familial cancer of breast	2024-01-10	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].