ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.1703G>T (p.Arg568Ile) (rs200381392)

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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 RCV000129176 SCV000183911 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-09 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other data supporting benign classification,In silico models in agreement (benign) ,Insufficient evidence
CeGaT Praxis fuer Humangenetik Tuebingen RCV000416037 SCV000493325 uncertain significance not provided 2016-08-31 criteria provided, single submitter clinical testing
Color RCV000129176 SCV000537515 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-18 criteria provided, single submitter clinical testing
Counsyl RCV000195658 SCV000799739 uncertain significance Ataxia-telangiectasia syndrome 2018-05-03 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515396 SCV000611346 uncertain significance Familial cancer of breast; Ataxia-telangiectasia syndrome 2017-05-23 criteria provided, single submitter clinical testing
GeneDx RCV000416037 SCV000209690 uncertain significance not provided 2018-12-24 criteria provided, single submitter clinical testing This variant is denoted ATM c.1703G>T at the cDNA level, p.Arg568Ile (R568I) at the protein level, and results in the change of an Arginine to an Isoleucine (AGA>ATA). This variant was observed in an individual with a personal and/or family history suggestive of Hereditary Breast and Ovarian Cancer (Cock-Rada 2018). ATM Arg568Ile was also identified in individuals with melanoma, breast, endometrial, and prostate cancer, as well as unaffected controls (Tung 2015, Decker 2017, Paulo 2018, Pritchard 2018, Yehia 2018). This variant was found to co-occur with an ATM frameshift variant in a patient with early-onset rectal cancer (Yurgelun 2017). ATM Arg568Ile was observed at an allele frequency of 0.34% (34/10,148) in individuals of Ashkenazi Jewish ancestry in large population cohorts (Lek 2016). This variant 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 Arg568Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000416037 SCV000694193 uncertain significance not provided 2017-08-15 criteria provided, single submitter clinical testing Variant summary: The ATM c.1703G>T (p.Arg568Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in the large control database ExAC in 17/121292 control chromosomes at a frequency of 0.0001402, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0010005). This variant was found in HBOC and rectal cancer patients without strong evidence for causality (Cock-Rada_2017, Yurgelun_2016). One of the reported patients was a 31 year old female with stage IV rectal cancer, mismatch repair proficient (MMR-P), WT KRAS, family history of cancer (mother, 58), in whom a co-occurring with pathogenic germline ATM variant, c.8934_8935del/p.E2979Afs*9 (not in our internal database) and the variant of interest in the ATM gene were identified. This variant was classified as a germline VUS by the authors, no information on the phase (cis vs trans) relative to the pathogenic ATM variant location, and no personal and/or a familial history on ataxia-telangiectasia was provided. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS.
Invitae RCV000195658 SCV000254062 benign Ataxia-telangiectasia syndrome 2018-01-04 criteria provided, single submitter clinical testing
Mendelics RCV000195658 SCV000838492 uncertain significance Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing

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