Submissions for variant NM_000051.4(ATM):c.6848C>T (p.Ser2283Leu)

gnomAD frequency: 0.00001  dbSNP: rs876660730

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000220834	SCV000278383	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-31	criteria provided, single submitter	clinical testing	The p.S2283L variant (also known as c.6848C>T), located in coding exon 46 of the ATM gene, results from a C to T substitution at nucleotide position 6848. The serine at codon 2283 is replaced by leucine, an amino acid with dissimilar properties. This alteration was detected in a patient with ovarian cancer and a patient with sebaceous adenoma in a cohort of 766 ATM variant carriers and classified as a variant of uncertain significance (Feliubadaló L et al. Clin Chem, 2021 Mar;67:518-533). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000559536	SCV000622692	uncertain significance	Ataxia-telangiectasia syndrome	2022-08-31	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 2283 of the ATM protein (p.Ser2283Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of hereditary cancer (PMID: 33280026). ClinVar contains an entry for this variant (Variation ID: 233915). 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.
Mendelics	RCV000559536	SCV000838581	uncertain significance	Ataxia-telangiectasia syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000220834	SCV000904845	uncertain significance	Hereditary cancer-predisposing syndrome	2021-01-26	criteria provided, single submitter	clinical testing	This missense variant replaces serine with leucine at codon 2283 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.
GeneDx	RCV001589160	SCV001815517	uncertain significance	not provided	2019-06-06	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28481359)
Spanish ATM Cancer Susceptibility Variant Interpretation Working Group	RCV000220834	SCV001911478	uncertain significance	Hereditary cancer-predisposing syndrome	2020-06-17	criteria provided, single submitter	clinical testing	The c.6848C>T (p.Ser2283Leu) variant is absent from the gnomAD v2.1.1 non-cancer dataset, in a position with adequate coverage (>20x) (PM2; http://gnomad.broadinstitute.org). It is not predicted to lead to a splicing alteration according to SPiCE, and no splicing site is created or activated according to at least 3 splicing predictors of the set SpliceSiteFinderlike - MaxEntScan - NNSplice - GeneSplicer. Also, this missense variant does not alter the protein function / structure on the in-silico prediction reports of REVEL and PROVEAN (BP4). There is no other supporting data that meet criteria for consideration. Therefore, the clinical significance of this variant is uncertain. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: PM2 + BP4 (PMID: 33280026).
Natera, Inc.	RCV000559536	SCV001458455	uncertain significance	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing