Submissions for variant NM_000051.4(ATM):c.4196C>G (p.Thr1399Ser)

dbSNP: rs786203761

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000215942	SCV000276255	likely benign	Hereditary cancer-predisposing syndrome	2024-02-15	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000473821	SCV000546704	uncertain significance	Ataxia-telangiectasia syndrome	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 1399 of the ATM protein (p.Thr1399Ser). 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: 232191). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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	RCV000486909	SCV000564639	uncertain significance	not provided	2018-10-10	criteria provided, single submitter	clinical testing	This variant is denoted ATM c.4196C>G at the cDNA level, p.Thr1399Ser (T1399S) at the protein level, and results in the change of a Threonine to a Serine (ACC>AGC). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. ATM Thr1399Ser was not observed in large population cohorts (Lek 2016). This variant is not located within 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 Thr1399Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000215942	SCV000682189	uncertain significance	Hereditary cancer-predisposing syndrome	2022-09-26	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with serine at codon 1399 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000486909	SCV002010817	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003462488	SCV004215529	uncertain significance	Familial cancer of breast	2023-12-19	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003491980	SCV004240680	uncertain significance	Breast and/or ovarian cancer	2022-09-14	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000473821	SCV002079258	uncertain significance	Ataxia-telangiectasia syndrome	2020-02-26	no assertion criteria provided	clinical testing