Submissions for variant NM_000051.4(ATM):c.7223C>T (p.Ser2408Leu)

dbSNP: rs730881315

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000159648	SCV000209638	uncertain significance	not provided	2024-03-12	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 17344846, 22529920, 27089234, 27245685, 23532176)
Ambry Genetics	RCV000215742	SCV000274174	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-13	criteria provided, single submitter	clinical testing	The p.S2408L variant (also known as c.7223C>T), located in coding exon 48 of the ATM gene, results from a C to T substitution at nucleotide position 7223. The serine at codon 2408 is replaced by leucine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Illumina Laboratory Services, Illumina	RCV000382704	SCV000367066	uncertain significance	Ataxia-telangiectasia syndrome	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000382704	SCV000546774	uncertain significance	Ataxia-telangiectasia syndrome	2023-12-12	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 2408 of the ATM protein (p.Ser2408Leu). This variant is present in population databases (rs730881315, gnomAD 0.003%). 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: 181888). 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 disruptive. 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	RCV000215742	SCV000682396	uncertain significance	Hereditary cancer-predisposing syndrome	2022-05-16	criteria provided, single submitter	clinical testing	This missense variant replaces serine with leucine at codon 2408 of the ATM protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, 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 been identified in 2/251186 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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002465538	SCV002760692	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004551368	SCV004109295	uncertain significance	ATM-related disorder	2023-06-09	criteria provided, single submitter	clinical testing	The ATM c.7223C>T variant is predicted to result in the amino acid substitution p.Ser2408Leu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-108199881-C-T) and has been reported in ClinVar as uncertain by many outside labs (https://www.ncbi.nlm.nih.gov/clinvar/variation/181888/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Baylor Genetics	RCV004567188	SCV005057039	uncertain significance	Familial cancer of breast	2024-01-30	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000159648	SCV005092476	uncertain significance	not provided	2024-07-01	criteria provided, single submitter	clinical testing	ATM: PM2, BP1
Natera, Inc.	RCV000382704	SCV002078152	uncertain significance	Ataxia-telangiectasia syndrome	2020-08-25	no assertion criteria provided	clinical testing