Submissions for variant NM_000051.4(ATM):c.2158C>T (p.Arg720Cys)

dbSNP: rs565622131

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000462183	SCV000546688	uncertain significance	Ataxia-telangiectasia syndrome	2023-12-30	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 720 of the ATM protein (p.Arg720Cys). This variant is present in population databases (rs565622131, gnomAD 0.01%). This missense change has been observed in individual(s) with breast cancer (PMID: 19781682). ClinVar contains an entry for this variant (Variation ID: 407475). 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 tolerated. 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.
GeneDx	RCV000481591	SCV000566507	uncertain significance	not provided	2024-01-22	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: 36243179, 19781682, 30287823)
Ambry Genetics	RCV000566565	SCV000660455	uncertain significance	Hereditary cancer-predisposing syndrome	2024-03-12	criteria provided, single submitter	clinical testing	The p.R720C variant (also known as c.2158C>T), located in coding exon 13 of the ATM gene, results from a C to T substitution at nucleotide position 2158. The arginine at codon 720 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in multiple individuals diagnosed with breast cancer (Tavtigian SV et al. Am. J. Hum. Genet. 2009 Oct;85:427-46; Hauke J et al. Cancer Med, 2018 04;7:1349-1358; Lerner-Ellis J et al. J Cancer Res Clin Oncol. 2021 147, 871–879). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000566565	SCV000906529	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-24	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 720 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: 19781682, 33471991), an individual with prostate cancer (PMID: 31214711), and individuals without cancer (PMID: 30287823, 31214711, 32980694, 33471991). This variant has been identified in 4/251022 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.
Baylor Genetics	RCV003470414	SCV004210288	uncertain significance	Familial cancer of breast	2024-03-06	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492052	SCV004240402	uncertain significance	Breast and/or ovarian cancer	2023-06-29	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355032	SCV001549791	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The ATM p.Arg720Cys variant was identified in 1 of 8224 proband chromosomes (frequency: 0.0001) from individuals or families with breast cancer and was not identified in 4792 control chromosomes from healthy individuals (Tavtigian 2009). The variant was identified in dbSNP (ID: rs565622131) “With Uncertain significance allele”, ClinVar (classified as uncertain significance by Invitae, GeneDx and Ambry Genetics) and LOVD 3.0 (3x). The variant was also identified in control databases in 4 of 245874 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 2 of 15296 chromosomes (freq: 0.0001), Latino in 1 of 33536 chromosomes (freq: 0.00003) and European Non-Finnish in 1 of 111552 chromosomes (freq: 0.000009); it was not observed in the Other, Ashkenazi Jewish, East Asian, European Finnish, or South Asian populations. The p.Arg720Cys residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.