ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.8113G>A (p.Val2705Ile) (rs587779870)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000115260 SCV000185078 uncertain significance Hereditary cancer-predisposing syndrome 2017-06-02 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000115260 SCV000687816 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-10 criteria provided, single submitter clinical testing
Counsyl RCV000234753 SCV000800164 uncertain significance Ataxia-telangiectasia syndrome 2018-05-23 criteria provided, single submitter clinical testing
GeneDx RCV000235110 SCV000149169 uncertain significance not provided 2018-01-23 criteria provided, single submitter clinical testing This variant is denoted ATM c.8113G>A at the cDNA level, p.Val2705Ile (V2705I) at the protein level, and results in the change of a Valine to an Isoleucine (GTA>ATA). This variant has been observed in at least one family with a history of breast and/or ovarian cancer as well as an individual with colorectal cancer (Tavera-Tapia 2017, Yurgelun 2017). ATM Val2705Ile was not observed at a significant allele frequency 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 Val2705Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000779774 SCV000916564 uncertain significance not specified 2017-12-26 criteria provided, single submitter clinical testing Variant summary: The ATM c.8113G>A (p.Val2705Ile) variant involves the alteration of a non-conserved nucleotide and is predicted to be benign by 3/3 in silico tools (SNPsandGO not captured due to low reliability index). This variant was found in 2/277112 control chromosomes (gnomAD) at a frequency of 0.0000072, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0010005). In literature, this variant has been reported in multiple individuals affected with breast and/or ovarian cancer or CRC without strong evidence for or against pathogenicity (Tung_2015, Tavera-Tapia_2017, Yurgelun_2017). Multiple clinical diagnostic laboratories/reputable databases and publications have classified this variant as uncertain significance. It has been found in internal sample that also carried another variant of unknown significance p.T417A. Taken together, this variant is currently classified as Variant of Unknown Significance.
Invitae RCV000234753 SCV000283072 uncertain significance Ataxia-telangiectasia syndrome 2018-11-27 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 2705 of the ATM protein (p.Val2705Ile). The valine residue is moderately conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs587779870, ExAC 0.001%). This variant has been reported in an individual affected with colorectal cancer (PMID: 28135145). ClinVar contains an entry for this variant (Variation ID: 127454). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The isoleucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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