ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.4505G>T (p.Cys1502Phe) (rs759340881)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000199907 SCV000254110 uncertain significance Ataxia-telangiectasia syndrome 2018-12-18 criteria provided, single submitter clinical testing This sequence change replaces cysteine with phenylalanine at codon 1502 of the ATM protein (p.Cys1502Phe). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and phenylalanine. This variant is present in population databases (rs759340881, ExAC 0.001%). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 216217). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; 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.
Ambry Genetics RCV000234909 SCV000276649 uncertain significance Hereditary cancer-predisposing syndrome 2017-06-24 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
GeneDx RCV000589257 SCV000278827 uncertain significance not provided 2018-12-13 criteria provided, single submitter clinical testing This variant is denoted ATM c.4505G>T at the cDNA level, p.Cys1502Phe (C1502F) at the protein level, and results in the change of a Cysteine to a Phenylalanine (TGC>TTC). This variant was observed in multiple individuals with breast cancer and in at least one control individual participating in a non-cancer study (Decker 2017, Engel 2018, Hauke 2018, Pritchard 2018). ATM Cys1502Phe was not observed in large population cohorts (Lek 2016). ATM Cys1502Phe 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 Cys1502Phe is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000234909 SCV000292214 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-02 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000589257 SCV000694285 uncertain significance not provided 2016-07-01 criteria provided, single submitter clinical testing Variant summary: The ATM c.4505G>T (p.Cys1502Phe) variant causes a missense change involving a conserved nucleotide with 4/4 in silico tools (SNPs&GO not captured due to low reliability index) predicting a "damaging" outcome, although these predictions have yet to be functionally assessed. The variant of interest is not known to be located in a functional domain (UniPort). The variant of interest was observed in the large, broad control population, ExAC, 1/121396, which does not exceed the estimated maximal expected allele frequency for a pathogenic ATM variant of 1/252 for Ataxia-Telangiectasisa or 1/1999 for BrC. The variant of interest has not, to our knowledge, been reported in affected individuals via publications, however, multiple reputable clinical laboratories cite variant as "uncertain significance." Therefore, taking all available lines of evidence into consideration, the variant of interest has been classified as "variant of uncertain significance," until additional information becomes available.

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