ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.7187C>G (p.Thr2396Ser) (rs370559102)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000115243 SCV000172917 uncertain significance Hereditary cancer-predisposing syndrome 2017-05-08 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (benign),Other data supporting benign classification
CeGaT Praxis fuer Humangenetik Tuebingen RCV000487700 SCV000574908 uncertain significance not provided 2017-02-28 criteria provided, single submitter clinical testing
Color RCV000115243 SCV000910619 likely benign Hereditary cancer-predisposing syndrome 2016-03-30 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000487700 SCV000861290 uncertain significance not provided 2018-05-14 criteria provided, single submitter clinical testing
GeneDx RCV000487700 SCV000149152 uncertain significance not provided 2018-11-15 criteria provided, single submitter clinical testing This variant is denoted ATM c.7187C>G at the cDNA level, p.Thr2396Ser (T2396S) at the protein level, and results in the change of a Threonine to a Serine (ACT>AGT). This variant has been identified in several individuals with a personal and/or family history of a breast cancer, but was also observed in healthy controls (Brunet 2008, Tavtigian 2009, Bernstein 2010, Paglia 2010, Tung 2015, Decker 2017). This variant has also been reported in at least one individual with a history of a Lynch syndrome-associated cancer and/or colon polyps, in an individual with endometrial cancer, and in two relatives with melanoma (Yurgelun 2015, Ring 2016, Goldstein 2017). ATM Thr2396Ser was observed at an allele frequency of 0.05% (16/34,416) in individuals of Latino 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 that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether ATM Thr2396Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
GeneKor MSA RCV000115243 SCV000821868 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000487700 SCV000694347 uncertain significance not provided 2017-05-22 criteria provided, single submitter clinical testing Variant summary: The ATM c.7187C>G (p.Thr2396Ser) variant indicated to be located in the FAT domain (Goldgar_2011) involves the alteration of a non-conserved nucleotide and 5/5 in silico tools predict a benign outcome for this variant. This variant was found in 24/126354 control chromosomes at a frequency of 0.0001899, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0010005). Multiple publications have cited the variant in affected individuals (BrC, Lynch syndrome, and CLL) with limited information (lack of co-occurrence and/or cosegregation data). It was found in one T-cell prolymphocytic leukaemia patient who also carried an ATM 4174insC mutation, however, neither the germline presence of the reported ATM variant (4174insC) nor a diagnosis or a family history of AT was reported. A large meta-analysis, Tavtigian_2009, indicates an unclear risk association for BrC (OR: 1.17). Multiple clinical diagnostic laboratories have classified the variant as "uncertain significance." Therefore, until additional information becomes available, the variant of interest has been classified as a "Variant of Uncertain Significance - Possibly Benign."
Invitae RCV000198387 SCV000254141 likely benign Ataxia-telangiectasia syndrome 2018-01-11 criteria provided, single submitter clinical testing
Mendelics RCV000198387 SCV000838589 uncertain significance Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing

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