ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.6503C>T (p.Ser2168Leu) (rs200431631)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000206774 SCV000261140 uncertain significance Ataxia-telangiectasia syndrome 2018-12-22 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 2168 of the ATM protein (p.Ser2168Leu). The serine residue is moderately conserved and there is a large physicochemical difference between serine and leucine. This variant is present in population databases (rs200431631, ExAC 0.06%). This variant has been observed in an individual affected with breast cancer (PMID: 28580595). ClinVar contains an entry for this variant (Variation ID: 220531). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
Ambry Genetics RCV000216900 SCV000274735 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-22 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Color RCV000216900 SCV000537533 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-26 criteria provided, single submitter clinical testing
GeneDx RCV000588892 SCV000568996 uncertain significance not provided 2018-12-31 criteria provided, single submitter clinical testing This variant is denoted ATM c.6503C>T at the cDNA level, p.Ser2168Leu (S2168L) at the protein level, and results in the change of a Serine to a Leucine (TCG>TTG). This variant has been observed in individuals with breast cancer, including male breast cancer, as well as colorectal cancer (Decker 2017, Momozawa 2018, Yehia 2018). ATM Ser2168Leu was also reported in a multi-ethnic exome array study; however, no statistically significant association with breast cancer was identified after correcting for multiple comparisons (Haiman 2013). ATM Ser2168Leu was observed at an allele frequency of 0.074% (14/18,868) in individuals of East Asian ancestry in large population cohorts (Lek 2016). This variant is located in the FAT domain (Stracker 2013). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether ATM Ser2168Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000588892 SCV000694325 uncertain significance not provided 2016-12-22 criteria provided, single submitter clinical testing Variant summary: The ATM c.6503C>T (p.Ser2168Leu) variant located in the PIK-related kinase domain (via InterPro) causes a missense change involving a conserved nucleotide, which 4/5 in silico tools predict a damaging outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 7/121406 (1/17343), predominantly in the East Asian cohort, 5/8648 (1/1729), which does not exceed the estimated maximal expected allele frequency for a pathogenic ATM variant of 1/999. The variant of interest has been reported by publications, although with limited information (ie, lack of co-occurrence/cosegregation data). Multiple clinical diagnostic laboratories have cited the variant as "uncertain significance." Therefore, until additional information becomes available (ie, clinical and functional studies), the variant of interest has been classified as a "Variant of Uncertain Significance (VUS)."
Mendelics RCV000206774 SCV000838574 uncertain significance Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763709 SCV000894589 uncertain significance Familial cancer of breast; Ataxia-telangiectasia syndrome 2018-10-31 criteria provided, single submitter clinical testing

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