ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.2T>C (p.Met1Thr) (rs786203606)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166992 SCV000217813 pathogenic Hereditary cancer-predisposing syndrome 2018-03-24 criteria provided, single submitter clinical testing The p.M1? pathogenic mutation (also known as c.2T>C), located in coding exon 1 of the ATM gene, results from a T to C substitution at nucleotide position 2. This alters the methionine residue at the initiation codon. This alteration has been reported in an individual with ovarian cancer (Crawford B et al. Breast Cancer Res. Treat., 2017 Jun;163:383-390), and also in compound heterozygous state in patients with ataxia telangiectasia (Gilad S et al. Hum. Mol. Genet., 1996 Apr;5:433-9; Buzin CH et al. Hum. Mutat., 2003 Feb;21:123-31; Byrd PJ et al. Br. J. Cancer, 2012 Jan;106:262-8). In addition to the clinical data presented in the literature, since sequence variations that modify the initiation codon (ATG) are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame, this alteration is interpreted as a disease-causing mutation.
Invitae RCV000168377 SCV000219068 pathogenic Ataxia-telangiectasia syndrome 2020-10-30 criteria provided, single submitter clinical testing This sequence change affects the initiator methionine of the ATM mRNA. This variant is not present in population databases (ExAC no frequency). This variant has been observed on the opposite chromosome (in trans) from pathogenic ATM variants in several individuals with ataxia-telangiectasia (PMID: 8845835, 12552559, 22649200, 9463314, 21792198). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. This variant is also referred to as p.(Met1Thr) in the literature. ClinVar contains an entry for this variant (Variation ID: 187275). Experimental studies have shown that this sequence change leads to markedly reduced expression of a smaller, truncated ATM protein with no kinase activity, likely explained by the use of an alternate downstream ATG (PMID: 22146522, 21593342, 21792198). For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000168377 SCV000221102 likely pathogenic Ataxia-telangiectasia syndrome 2015-01-29 criteria provided, single submitter literature only
GeneDx RCV000519260 SCV000616967 pathogenic not provided 2018-12-10 criteria provided, single submitter clinical testing This variant, denoted ATM c.2T>C at the cDNA level, alters the initiator Methionine codon, and the resultant protein would be described as ?p.Met1?? to signify that it is not known if the loss of Met1 prevents all protein translation or if an abnormal protein is produced using an alternate Methionine codon. This variant, also reported as ATM Met1Thr in the literature, has been observed with a second ATM variant in multiple individuals with ataxia-telangiectasia (Stankovic 1998, Buzin 2003, Exley 2011, Reiman 2011). It has also been observed in individuals with breast, ovarian, prostate, and brain cancer (Crawford 2017, Decker 2017, Gardner 2018, Waszak 2018, Zafeiriou 2019). Functional studies of this variant have demonstrated the possible use of a downstream initiation codon, resulting in trace levels of a truncated protein with no kinase activity, while other studies have shown completely absent protein production (Stankovic 1998, Exley 2011, Reiman 2011, Byrd 2012, Carney 2012). We consider this variant to be pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000168377 SCV000694244 pathogenic Ataxia-telangiectasia syndrome 2016-01-25 criteria provided, single submitter clinical testing
Color Health, Inc RCV000166992 SCV000905152 pathogenic Hereditary cancer-predisposing syndrome 2020-09-01 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 over ten individuals affected with ataxia-telangiectasia in compound heterozygous state with pathogenic mutations (PMID: 8845835, 9463314, 12552559, 15928302, 21593342, 21792198, 22146522, 22649200, 30549301). In cell lines derived from these individuals, a very low level of expression of a truncated ATM protein was observed, probably due to the use of an alternate downstream methionine (PMID: 21593342, 21792198, 22146522). There was no detectable kinase activity in these cell lines. This variant has also been observed in individuals affected with breast cancer (PMID: 28779002, 29308099), ovarian cancer (PMID: 28281021) and brain cancer (PMID 29753700). This variant has been identified in 1/251392 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
GeneReviews RCV000168377 SCV000328296 pathogenic Ataxia-telangiectasia syndrome 2016-10-27 no assertion criteria provided literature only
Natera, Inc. RCV000168377 SCV001461801 pathogenic Ataxia-telangiectasia syndrome 2020-09-16 no assertion criteria provided clinical testing

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