ClinVar Miner

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

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Total submissions: 7
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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 Lines of evidence used in support of classification: Other acmg-defined mutation (i.e. initiation codon or gross deletion)
Color RCV000166992 SCV000905152 pathogenic Hereditary cancer-predisposing syndrome 2015-04-27 criteria provided, single submitter clinical testing
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.
GeneReviews RCV000168377 SCV000328296 pathogenic Ataxia-telangiectasia syndrome 2016-10-27 no assertion criteria provided literature only
Integrated Genetics/Laboratory Corporation of America RCV000168377 SCV000694244 pathogenic Ataxia-telangiectasia syndrome 2016-01-25 criteria provided, single submitter clinical testing
Invitae RCV000168377 SCV000219068 pathogenic Ataxia-telangiectasia syndrome 2018-12-27 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.

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