ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.4148C>T (p.Ser1383Leu) (rs141087784)

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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 RCV000115187 SCV000184168 uncertain significance Hereditary cancer-predisposing syndrome 2017-10-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,Insufficient evidence
Color RCV000115187 SCV000537543 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-15 criteria provided, single submitter clinical testing
GeneDx RCV000212009 SCV000149096 uncertain significance not provided 2017-09-18 criteria provided, single submitter clinical testing This variant is denoted ATM c.4148C>T at the cDNA level, p.Ser1383Leu (S1383L) at the protein level, and results in the change of a Serine to a Leucine (TCG>TTG). This variant was observed in individuals with breast cancer in multiple studies with no segregation data available (Teraoka 2001, Angele 2003, Gutierrez-Enriquez 2004, Tavtigian 2009, Tung 2016, Rummel 2017), as well as in individuals with lung adenocarcinoma or chronic lymphocytic leukemia (Lu 2015, Nadeu 2016). Tavtigian et al. (2009) observed this variant in combination with another missense variant, ATM Asp1853Val, in the absence of Ataxia-telangiectasia. ATM Ser1383Leu was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Serine and Leucine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Ser1383Leu occurs at a position that is conserved across species and is not located in a known functional domain. In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether ATM Ser1383Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000780883 SCV000918511 uncertain significance not specified 2017-09-07 criteria provided, single submitter clinical testing Variant summary: The c.4148C>T (p.Ser1383Leu) in ATM gene is a missense change that involves a conserved nucleotide and 4/4 in silico tools predict deleterious outcome (SNPsandGO not captured due to low reliability index). The variant is located outside of any known functional domain or repeat. The variant is present at a low frequency in control population dataset of ExAC (0.00004; 5/66692 chrs tested), which does not exceed the maximum expected allele frequency for a pathogenic variant of 0.0013. The variant was identified in several cancer patients without strong evidence for causality (eg, lack of segregation/co-occurrence information). In addition, the variant was identified in internal sample with positive personal and family history of BrC (paternal aunt, greatmother) in co-occurrence with a known pathogenic variant in BRCA2 c.9256_9256+1delinsTA. Lastly, the variant of interest has been reported as VUS by reputable database/clinical laboratories and published reports. Taking together, since the role of the variant in carcinogenesis remains unclear, the variant was classified as VUS.
Invitae RCV000459643 SCV000546705 uncertain significance Ataxia-telangiectasia syndrome 2018-12-28 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 1383 of the ATM protein (p.Ser1383Leu). The serine residue is highly conserved and there is a large physicochemical difference between serine and leucine. This variant is present in population databases (rs141087784, ExAC 0.01%). This variant has been reported in individuals with breast cancer, chronic lymphocytic leukemia, and lung cancer (PMID: 11505391, 19781682, 26976419, 14695186, 26837699, 26689913, 15101044). This variant occurred with a pathogenic variant in ATM in an individual affected with bladder cancer, but unaffected with ataxia-telangiectasia (Invitae). While it is unknown if these variants were on the same or opposite chromosomes, this observation suggests that the c.4148C>T variant was not a primary cause of disease in that individual. ClinVar contains an entry for this variant (Variation ID: 127382). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65"). 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.
Mendelics RCV000459643 SCV000838536 uncertain significance Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing
PreventionGenetics RCV000212009 SCV000805556 uncertain significance not provided 2017-12-07 criteria provided, single submitter clinical testing

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