Submissions for variant NM_000051.4(ATM):c.1099T>C (p.Ser367Pro)

dbSNP: rs879254236

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000236390	SCV000293924	uncertain significance	not provided	2016-02-08	criteria provided, single submitter	clinical testing	This variant is denoted ATM c.1099T>C at the cDNA level, p.Ser367Pro (S367P) at the protein level, and results in the change of a Serine to a Proline (TCT>CCT). This variant has not, to our knowledge, been published in the literature as either a mutation or a benign polymorphism. ATM Ser367Pro was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Serine and Proline differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Ser367Pro occurs at a position where amino acids with properties similar to Serine are tolerated across species and is not located in a known functional domain (Tavtigian 2009), however it is located at a site of autophosphorylation (Kozlov 2011). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether ATM Ser367Pro is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001857816	SCV002205719	uncertain significance	Ataxia-telangiectasia syndrome	2022-02-25	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 367 of the ATM protein (p.Ser367Pro). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 246391). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ATM protein function. 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	RCV004678655	SCV005180321	likely benign	Hereditary cancer-predisposing syndrome	2024-06-11	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.