Submissions for variant NM_000051.4(ATM):c.2849T>G (p.Leu950Arg)

dbSNP: rs786203054

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166191	SCV000216968	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-07-06	criteria provided, single submitter	clinical testing	The p.L950R variant (also known as c.2849T>G), located in coding exon 18 of the ATM gene, results from a T to G substitution at nucleotide position 2849. The leucine at codon 950 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been reported in multiple individuals diagnosed with ataxia telangiectasia (Becker-Catania SG et al. Mol. Genet. Metab. 2000 Jun;70:122-33; Buzin CH et al. Hum. Mutat. 2003 Feb;21:123-31; Reiman A et al. Br. J. Cancer 2011 Aug;105(4):586-91). This alteration was reported in a patient diagnosed with breast cancer as well as patient with localized prostate cancer (Yadav S et al. J Clin Oncol. 2020 05;38:1409-1418; Na R et al. Eur. Urol. 2017 May;71:740-747). Two studies have demonstrated that this alteration leads to lack of ATM protein expression (Becker-Catania SG et al. Mol. Genet. Metab. 2000 Jun;70:122-33; Fang Z et al. Genome Integr. 2010 Jun;1:9). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
GeneDx	RCV000255989	SCV000321411	likely pathogenic	not provided	2023-06-27	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; This variant is associated with the following publications: (PMID: 21792198, 10330348, 30128536, 10873394, 20678261, 15928302, 27989354, 27304073, 28873162, 19781682, 34771661, 27535533, 32125938, 12552559, 36346689)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000628016	SCV000748903	likely pathogenic	Ataxia-telangiectasia syndrome	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 950 of the ATM protein (p.Leu950Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with pancreatic cancer and ataxia-telangiectasia (PMID: 10873394, 12552559, 20678261, 21792198, 27989354). ClinVar contains an entry for this variant (Variation ID: 186574). 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. Experimental studies have shown that this missense change affects ATM function (PMID: 10873394, 20678261). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000166191	SCV000913907	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-04-07	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with arginine at codon 950 in the beta-adaptin interaction domain of the ATM protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with ataxia telangiectasia (PMID: 10873394, 12552559, 20678261, 21792198), breast cancer (Color internal data), and prostate cancer (PMID: 27989354). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Revvity Omics, Revvity	RCV000628016	SCV002024400	likely pathogenic	Ataxia-telangiectasia syndrome	2019-05-06	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003468776	SCV004210219	likely pathogenic	Familial cancer of breast	2024-02-06	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003468776	SCV004931387	likely pathogenic	Familial cancer of breast	2024-01-23	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 10873394, 21792198, 20678261]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 10873394, 21792198, 12552559, 20678261].
GenomeConnect - Invitae Patient Insights Network	RCV003483541	SCV004228705	not provided	Familial cancer of breast; Ataxia-telangiectasia syndrome		no assertion provided	phenotyping only	Variant interpreted as Likely pathogenic and reported on 03-14-2020 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.