ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.1943T>C (p.Val648Ala) (rs141175037)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000195774 SCV000254065 uncertain significance Ataxia-telangiectasia syndrome 2019-10-24 criteria provided, single submitter clinical testing This sequence change replaces valine with alanine at codon 648 of the ATM protein (p.Val648Ala). The valine residue is moderately conserved and there is a small physicochemical difference between valine and alanine. This variant is present in population databases (rs141175037, ExAC 0.002%). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 216193). 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 alanine 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.
Ambry Genetics RCV000221613 SCV000274293 uncertain significance Hereditary cancer-predisposing syndrome 2018-11-13 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
GeneDx RCV000479071 SCV000569225 uncertain significance not provided 2017-05-05 criteria provided, single submitter clinical testing This variant is denoted ATM c.1943T>C at the cDNA level, p.Val648Ala (V648A) at the protein level, and results in the change of a Valine to an Alanine (GTA>GCA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Val648Ala was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Valine and Alanine share similar properties, this is considered a conservative amino acid substitution. ATM Val648Ala occurs at a position where amino acids with properties similar to Valine are tolerated across species and is not located in a known functional domain. In silico analyses are inconsistent regarding the effect this variant may have on protein structure or function. Based on currently available evidence, it is unclear whether ATM Val648Ala is pathogenic or benign. We consider it to be a variant of uncertain significance.
Counsyl RCV000195774 SCV000788939 uncertain significance Ataxia-telangiectasia syndrome 2016-12-22 criteria provided, single submitter clinical testing
Color RCV000221613 SCV000913554 uncertain significance Hereditary cancer-predisposing syndrome 2019-08-22 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000780905 SCV000918543 uncertain significance not specified 2020-08-04 criteria provided, single submitter clinical testing Variant summary: ATM c.1943T>C (p.Val648Ala) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251240 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1943T>C has been reported in the literature in a healthy control individual (Tiao 2017). This report does not provide unequivocal conclusions about association of the variant with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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