Submissions for variant NM_000051.4(ATM):c.1792A>G (p.Ile598Val)

gnomAD frequency: 0.00002  dbSNP: rs730881343

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000211969	SCV000209692	uncertain significance	not provided	2023-12-01	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22420423, 29641532, 36243179, 32055024)
Ambry Genetics	RCV000159686	SCV000217865	likely benign	Hereditary cancer-predisposing syndrome	2023-11-28	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	RCV000462248	SCV000546734	uncertain significance	Ataxia-telangiectasia syndrome	2024-01-04	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 598 of the ATM protein (p.Ile598Val). This variant is present in population databases (rs730881343, gnomAD 0.003%). This missense change has been observed in individual(s) with breast cancer (PMID: 22420423). ClinVar contains an entry for this variant (Variation ID: 181921). 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 valine 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	RCV000159686	SCV000681999	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-06	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with valine at codon 598 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 been reported in individuals affected with breast cancer (PMID: 22420423, 33471991) and in unaffected individuals (PMID: 29641532, 33471991). This variant has been identified in 1/249850 chromosomes 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780876	SCV000918501	uncertain significance	not specified	2017-10-12	criteria provided, single submitter	clinical testing	Variant summary: The c.1792A>G (p.Ile598Val) in ATM gene is a missense variant involves a non-conserved nucleotide and 5/5 in silico tools predict benign outcome. The variant is located outside of any known domain or repeat, and no functional studied suggesting the impact of this change on protein function were published at the time of evaluation. The c.1792A>G is present in the control population dataset of gnomAD at a low frequency of 0.000004 (1/ 245020 chrs tested), which frequency does not exceed the maximum expected allele frequency for a pathogenic variant of 0.001. The variant has been reported in at least one brC patient without strong evidence for causality. Lastly, the variant of interest is cited as VUS by reputable databases/clinical laboratories. Taken together, due to the lack of supportive evidence, the variant was classified as VUS, until new information becomes available.
Natera, Inc.	RCV000462248	SCV002083846	uncertain significance	Ataxia-telangiectasia syndrome	2020-08-28	no assertion criteria provided	clinical testing