ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.4768C>T (p.Leu1590Phe) (rs35962982)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000589456 SCV000209741 uncertain significance not provided 2018-09-11 criteria provided, single submitter clinical testing This variant is denoted ATM c.4768C>T at the cDNA level, p.Leu1590Phe (L1590F) at the protein level, and results in the change of a Leucine to a Phenylalanine (CTC>TTC). This variant has been reported in several individuals with breast or colorectal cancer (Tung 2015, Pearlman 2017, Yurgelun 2017, Goidescu 2018, Hauke 2018, Yehia 2018), but has also been observed in healthy controls (Tiao 2017, Pritchard 2018). ATM Leu1590Phe was observed at an allele frequency of 0.036% (45/126,136) in individuals of European 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 a deleterious effect. Based on currently available evidence, it is unclear whether ATM Leu1590Phe is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000159728 SCV000216290 uncertain significance Hereditary cancer-predisposing syndrome 2017-06-29 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
Invitae RCV000196470 SCV000254114 uncertain significance Ataxia-telangiectasia syndrome 2019-01-04 criteria provided, single submitter clinical testing This sequence change replaces leucine with phenylalanine at codon 1590 of the ATM protein (p.Leu1590Phe). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is present in population databases (rs35962982, ExAC 0.04%). This variant has been observed in an individual affected with breast cancer who also carried a pathogenic variants in CHEK2 and BLM (PMID: 29785153). Additionally, this variant has been observed in individuals affected with colorectal cancer (PMID: 27978560, 28135145) as well as unaffected individuals (PMID: 28652578). This variant is referred to as c.4768C>T (p.L1690F) in the literature. ClinVar contains an entry for this variant (Variation ID: 181961). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). 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.
Fulgent Genetics,Fulgent Genetics RCV000515177 SCV000611364 uncertain significance Familial cancer of breast; Ataxia-telangiectasia syndrome 2017-05-23 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000589456 SCV000694291 uncertain significance not provided 2016-03-21 criteria provided, single submitter clinical testing
Counsyl RCV000196470 SCV000800038 uncertain significance Ataxia-telangiectasia syndrome 2018-05-21 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000589456 SCV000805571 uncertain significance not provided 2017-10-26 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000589456 SCV001148428 uncertain significance not provided 2018-10-01 criteria provided, single submitter clinical testing

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