ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.2333A>G (p.Asn778Ser) (rs587779820)

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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 RCV000115153 SCV000185280 uncertain significance Hereditary cancer-predisposing syndrome 2017-11-14 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000115153 SCV000911181 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-24 criteria provided, single submitter clinical testing
GeneDx RCV000589935 SCV000149062 uncertain significance not provided 2018-02-16 criteria provided, single submitter clinical testing This variant is denoted ATM c.2333A>G at the cDNA level, p.Asn778Ser (N778S) at the protein level, and results in the change of an Asparagine to a Serine (AAT>AGT). This variant has been observed in at least one individual with a history of pancreatic cancer (Grant 2015). ATM Asn778Ser was not observed at a significant allele frequency in large population cohorts (Lek 2016). ATM Asn778Ser 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 Asn778Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Illumina Clinical Services Laboratory,Illumina RCV000195938 SCV000367036 uncertain significance Ataxia-telangiectasia syndrome 2016-06-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000589935 SCV000694217 uncertain significance not provided 2017-08-21 criteria provided, single submitter clinical testing Variant summary: The ATM c.2333A>G (p.Asn778Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide located in the Armadillo-type fold domain (IPR016024) (InterPro). 4/4 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 1/121360 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0010005). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. This variant was reported in patients with breast, ovarian, and pancreatic cancer without strong evidence for causality (Bernstein_2010, Grant_2015, Lu_2015, Tung_2015). The variant of interest has not, to our knowledge, been reported in affected individuals via reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. This variant is classified as a variant of uncertain significance (VUS) until more clinical and functional studies become available.
Invitae RCV000195938 SCV000254068 uncertain significance Ataxia-telangiectasia syndrome 2018-07-09 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 778 of the ATM protein (p.Asn778Ser). The asparagine residue is weakly conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs587779820, ExAC 0.001%). This variant has been observed in individuals affected with ovarian, breast, and pancreatic cancers (PMID: 26689913, 25186627, 20305132, 25479140). ClinVar contains an entry for this variant (Variation ID: 127348). 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 serine 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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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