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
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.
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
Invitae RCV000487700 SCV000254141 benign not provided 2019-03-05 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000487700 SCV000574908 uncertain significance not provided 2017-01-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000855569 SCV000694347 uncertain significance not specified 2019-01-22 criteria provided, single submitter clinical testing Variant summary: The variant, ATM c.7187C>G (p.Thr2396Ser) results in a conservative amino acid change located in the FAT domain (IPR003151) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0002 in 282360 control chromosomes (gnomAD, Brunet 2008 and Tavtigian 2009). This frequency is not higher than expected for a pathogenic variant in ATM causing Breast Cancer (0.0002 vs 0.001), allowing no conclusion about variant significance. In addition, the variant was also reported in 3/7325 European American women (i.e. with a frequency of 0.00041), who were older than 70 years of age, and never had cancer (in the FLOSSIES database). Multiple publications have cited the variant in affected individuals (breast cancer, ovarian cancer, melanoma and CLL) with limited information (i.e. lack of co-occurrence and/or cosegregation data) (e.g. Paglia 2010, Tavera-Tapia 2017, Goldstein 2017, Tiao 2017, Hauke 2018). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (classifying the variant as VUS (6x) and Likely benign (1x)). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
GeneKor MSA RCV000115243 SCV000821868 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Mendelics RCV000198387 SCV000838589 uncertain significance Ataxia-telangiectasia syndrome 2018-07-02 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
Color RCV000115243 SCV000910619 likely benign Hereditary cancer-predisposing syndrome 2016-03-30 criteria provided, single submitter clinical testing

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