Submissions for variant NM_000051.4(ATM):c.6577G>A (p.Val2193Ile)

dbSNP: rs754555043

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000215163	SCV000275997	likely benign	Hereditary cancer-predisposing syndrome	2024-03-14	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.
GeneDx	RCV000235792	SCV000293880	uncertain significance	not provided	2018-01-05	criteria provided, single submitter	clinical testing	This variant is denoted ATM c.6577G>A at the cDNA level, p.Val2193Ile (V2193I) at the protein level, and results in the change of a Valine to an Isoleucine (GTC>ATC). This variant was observed in a blood sample from a patient with leukemia (McKeown 2017). ATM Val2193Ile was not observed in large population cohorts (Lek 2016). This variant is located in within the FAT domain (Stracker 2013). 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 Val2193Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000461049	SCV000546748	uncertain significance	Ataxia-telangiectasia syndrome	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 2193 of the ATM protein (p.Val2193Ile). 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: 231987). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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.
Color Diagnostics, LLC DBA Color Health	RCV000215163	SCV000904710	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-20	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 2193 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.