ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.4060C>A (p.Pro1354Thr) (rs145119475)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000115184 SCV000185799 uncertain significance Hereditary cancer-predisposing syndrome 2018-02-14 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000115184 SCV000902664 likely benign Hereditary cancer-predisposing syndrome 2015-01-16 criteria provided, single submitter clinical testing
GeneDx RCV000656759 SCV000149093 uncertain significance not provided 2018-10-30 criteria provided, single submitter clinical testing This variant is denoted ATM c.4060C>A at the cDNA level, p.Pro1354Thr (P1354T) at the protein level, and results in the change of a Proline to a Threonine (CCA>ACA). This variant has been observed in several individuals with breast cancer, but was also identified in healthy controls (Tavitigan 2009, Decker 2017, Hauke 2018). This variant has also been reported in an individual with kidney cancer and an individual with lung cancer (Lu 2015). ATM Pro1354Thr was observed at an allele frequency of 0.036% (45/124,128) in individuals of European ancestry in large population cohorts (Lek 2016). ATM Pro1354Thr is not located in a known functional domain. 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 Pro1354Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Genetic Services Laboratory, University of Chicago RCV000193232 SCV000246617 uncertain significance not specified 2015-01-21 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000193232 SCV000918509 uncertain significance not specified 2017-09-15 criteria provided, single submitter clinical testing Variant summary: The ATM c.4060C>A (p.Pro1354Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. 2/3 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). The variant was found in the control population dataset of ExAC in 26/125810 control chromosomes at a frequency of 0.0002067, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0010005). This variant was reported in multiple breast, ovarian, kidney, and lung cancer patients but also in controls, without strong evidence for causality (Tavera-Tapia_2017, Tavtigian_2009, Bernstein_ 2010, Lu_2015). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS, until more definitive clinical and functional studies become available.
Invitae RCV000168271 SCV000218943 benign Ataxia-telangiectasia syndrome 2018-01-12 criteria provided, single submitter clinical testing
Mendelics RCV000168271 SCV000838531 uncertain significance Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing
PreventionGenetics RCV000656759 SCV000805552 uncertain significance not provided 2018-01-08 criteria provided, single submitter clinical testing

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