ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.1132A>G (p.Ser378Gly) (rs587779811)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000561450 SCV000672640 likely benign Hereditary cancer-predisposing syndrome 2017-07-28 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other strong data supporting benign classification,In silico models in agreement (benign)
Color RCV000561450 SCV000903186 likely benign Hereditary cancer-predisposing syndrome 2017-02-16 criteria provided, single submitter clinical testing
GeneDx RCV000115134 SCV000149043 uncertain significance not provided 2017-02-03 criteria provided, single submitter clinical testing This variant is denoted ATM c.1132A>G at the cDNA level, p.Ser378Gly (S378G) at the protein level, and results in the change of a Serine to a Glycine (AGT>GGT). This variant has been reported in a woman with unilateral breast cancer and was identified on a cancer panel testing in an individual with a personal and/or family history suggestive of a hereditary cancer syndrome (Broeks 2008, Yorczyk 2014). ATM Ser378Gly was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Serine and Glycine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Ser378Gly occurs at a position that is not conserved and is not located in a known functional domain. In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether ATM Ser378Gly is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000477027 SCV000547125 uncertain significance Ataxia-telangiectasia syndrome 2018-06-28 criteria provided, single submitter clinical testing This sequence change replaces serine with glycine at codon 378 of the ATM protein (p.Ser378Gly). The serine residue is weakly conserved and there is a small physicochemical difference between serine and glycine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with breast cancer (PMID: 197781682, 17393301, 25318351). ClinVar contains an entry for this variant (Variation ID: 127330). 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 glycine amino acid residue is also 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. In summary, this variant is a rare missense change that is not predicted to affect protein function. While it is absent from the population and reported in affected individuals, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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