ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.8578_8580delTCT (p.SER1512DEL) (rs786203976)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000167512 SCV000218370 uncertain significance Hereditary cancer-predisposing syndrome 2016-11-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Deficient protein function in appropriate functional assay(s),Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Deficient protein function by in vitro/ex vivo assay,Detected in individual(s) satisfying established diagnostic criteria for classic disease in trans with a mutation or mutation is homozygous
Color RCV000167512 SCV000682502 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-18 criteria provided, single submitter clinical testing
GeneDx RCV000480186 SCV000568341 uncertain significance not provided 2016-06-13 criteria provided, single submitter clinical testing This in-frame deletion of 3 nucleotides in ATM is denoted c.8578_8580delTCT at the cDNA level and p.Ser2860del (S2860del) at the protein level. The normal sequence, with the bases that are deleted in braces, is TTCT[TCT]ATTG. This deletion of a single Serine residue occurs at a position that is conserved across species and is located in the PI3-PI4 kinase domain (Tavtigian 2009, Stracker 2013). This variant was observed in the compound heterozygous state in three individuals with non-classical ataxia-telangiectasia (Verhagen 2012, Kuhm 2015). Western blot analysis of lymphoblast cell lines from two patients showed presence of ATM protein but absence of kinase activity (Verhagen 2012). Since in-frame deletions may or may not inhibit proper protein functioning, the clinical significance of this finding remains unclear at this time and we consider ATM Ser2860del to be a variant of uncertain significance.
Invitae RCV000003154 SCV000546693 uncertain significance Ataxia-telangiectasia syndrome 2018-03-12 criteria provided, single submitter clinical testing This sequence change deletes 3 nucleotides from exon 58 of the ATM mRNA (c.8578_8580delTCT). This leads to the deletion of 1 amino acid residue in the ATM protein (p.Ser2860del) but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (ExAC no frequency). This variant has been observed on the opposite chromosome (in trans) from a pathogenic variant in an individual affected with generalized dystonia (PMID: 25572163). In two individuals affected with ataxia-telangiectasia, this variant was reported to co-occur with a different pathogenic ATM variant in each case, although it is uncertain whether the two variants are on the same or opposite chromosome (PMID: 19535770, 22213089). ClinVar contains an entry for this variant (Variation ID: 3018). Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the deleted amino acid is currently unknown. However, cell lines derived from individuals with ataxia-telangiectasia (PMID: 19535770), which carried this variant along with a known pathogenic ATM variant, exhibited low levels of ATM protein expression and lacked ATM kinase activity (PMID: 21792198, 22213089). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
OMIM RCV000003154 SCV000023312 pathogenic Ataxia-telangiectasia syndrome 1995-06-23 no assertion criteria provided literature only

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