ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.2921C>T (p.Ser974Phe) (rs538105098)

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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 RCV000165935 SCV000216691 uncertain significance Hereditary cancer-predisposing syndrome 2019-03-18 criteria provided, single submitter clinical testing Insufficient evidence
Invitae RCV000460970 SCV000546874 uncertain significance Ataxia-telangiectasia syndrome 2019-11-21 criteria provided, single submitter clinical testing This sequence change replaces serine with phenylalanine at codon 974 of the ATM protein (p.Ser974Phe). The serine residue is moderately conserved and there is a large physicochemical difference between serine and phenylalanine. This variant is present in population databases (rs538105098, ExAC 0.002%). This variant has been observed in an individual affected with breast cancer as well as in an unaffected control (PMID: 30287823). ClinVar contains an entry for this variant (Variation ID: 186354). 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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus 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.
GeneDx RCV000478958 SCV000567728 uncertain significance not provided 2018-05-23 criteria provided, single submitter clinical testing This variant is denoted ATM c.2921C>T at the cDNA level, p.Ser974Phe (S974F) at the protein level, and results in the change of a Serine to a Phenylalanine (TCC>TTC). This variant has not, to our knowledge, been published in the literature as either a pathogenic germline variant or a benign polymorphism. However, it has been reported as a somatic variant in a colorectal tumor (Yu 2015) and a head and neck squamous cell carcinoma (Stransky 2011). ATM Ser974Phe was not observed at a significant frequency in large population cohorts (Lek 2016). ATM Ser974Phe is located in the beta-adaptin interaction domain (Tavtigian 2009). Protein-based in silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. In addition, multiple splicing models predict that this variant may damage or destroy the nearby natural splice donor site. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. Based on currently available information, it is unclear whether ATM Ser974Phe is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color RCV000165935 SCV000913910 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-27 criteria provided, single submitter clinical testing

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