Submissions for variant NM_000051.4(ATM):c.8155C>T (p.Arg2719Cys)

gnomAD frequency: 0.00001  dbSNP: rs138526014

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165327	SCV000216050	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-12	criteria provided, single submitter	clinical testing	The p.R2719C variant (also known as c.8155C>T), located in coding exon 55 of the ATM gene, results from a C to T substitution at nucleotide position 8155. The arginine at codon 2719 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration was previously reported in 1/278 BRCA1/2-negative individuals with early-onset breast cancer via multiplex panel testing of 22 cancer susceptibility genes (Maxwell KN et al. Genet. Med. 2015 Aug;17:630-8). It was also detected in 1/4112 breast cancer patients and 0/2399 healthy control individuals across numerous studies (Tavtigian SV et al. Am. J. Hum. Genet. 2009 Oct;85:427-46). This alteration has been reported in at least one subject in a study of 13087 breast cancer cases and 5488 control individuals in the UK (Decker B et al. J. Med. Genet., 2017 11;54:732-741). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000457425	SCV000547025	uncertain significance	Ataxia-telangiectasia syndrome	2024-02-01	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 2719 of the ATM protein (p.Arg2719Cys). This variant is present in population databases (rs138526014, gnomAD 0.002%). This missense change has been observed in individual(s) with breast cancer (PMID: 25503501). ClinVar contains an entry for this variant (Variation ID: 185832). 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	RCV000165327	SCV000682463	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-02	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 2719 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 been reported in several individuals affected with breast cancer, including one early-onset individual (PMID: 25503501, 28779002). This variant has been identified in 3/250828 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.
Counsyl	RCV000457425	SCV000799931	uncertain significance	Ataxia-telangiectasia syndrome	2018-05-15	criteria provided, single submitter	clinical testing
Mendelics	RCV002247570	SCV002517884	uncertain significance	not specified	2022-05-04	criteria provided, single submitter	clinical testing
GeneDx	RCV001529786	SCV003805485	uncertain significance	not provided	2023-02-24	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; Identified in individuals with breast cancer (Maxwell et al., 2015; Decker et al., 2017); This variant is associated with the following publications: (PMID: 25503501, 23532176, 15279808, 28779002)
Laboratory of Medical Genetics Unit, Bambino Gesù Children's Hospital	RCV003313782	SCV004012971	uncertain significance	Astrocytoma IDH-mutant	2022-05-02	criteria provided, single submitter	research
Baylor Genetics	RCV003468741	SCV004210185	uncertain significance	Familial cancer of breast	2024-03-13	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002247570	SCV005089825	uncertain significance	not specified	2024-07-31	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000457425	SCV001462603	uncertain significance	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001529786	SCV001743857	uncertain significance	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV001529786	SCV001806850	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV001529786	SCV001906085	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV001529786	SCV001918582	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001529786	SCV001953724	uncertain significance	not provided		no assertion criteria provided	clinical testing