Submissions for variant NM_000051.4(ATM):c.3505G>A (p.Glu1169Lys)

gnomAD frequency: 0.00001  dbSNP: rs200765255

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166372	SCV000217162	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-12	criteria provided, single submitter	clinical testing	The p.E1169K variant (also known as c.3505G>A), located in coding exon 23 of the ATM gene, results from a G to A substitution at nucleotide position 3505. The glutamic acid at codon 1169 is replaced by lysine, an amino acid with similar properties. This alteration was detected in a cohort of 523 Italian male breast cancer patients (Rizzolo P et al. Int J Cancer, 2019 Jul;145:390-400). This alteration was also identified in a cohort of 1040 patients with advanced cancer; however, specific clinical information on this individual was not provided (Mandelker D et al. JAMA, 2017 09;318:825-835). This alteration has been reported in non-cancer control individuals in multiple studies and was absent in a cohort of patients with cutaneous melanoma and a history of at least two additional non-cutaneous melanoma primary cancers, a male breast cancer cohort, a prostate cancer cohort, as well as a chronic lymphocytic leukemia cohort respectively (Tiao G et al. Leukemia, 2017 Oct;31:2244-2247; Pritchard AL et al. PLoS One, 2018 Apr;13:e0194098; Momozawa Y et al. Nat Commun, 2018 10;9:4083; Momozawa Y et al. J Natl Cancer Inst, 2020 Apr;112:369-376). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000204598	SCV000260878	uncertain significance	Ataxia-telangiectasia syndrome	2024-01-20	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1169 of the ATM protein (p.Glu1169Lys). This variant is present in population databases (rs200765255, gnomAD 0.0009%). This missense change has been observed in individual(s) with male breast cancer and other unspecified cancer (PMID: 28873162, 30613976). ClinVar contains an entry for this variant (Variation ID: 186729). 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. 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 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	RCV000413647	SCV000490414	uncertain significance	not provided	2023-04-19	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 male breast and other cancers (Rizzolo et al., 2019; Mandelker et al., 2017); This variant is associated with the following publications: (PMID: 28652578, 28873162, 30287823, 31214711, 30613976)
Color Diagnostics, LLC DBA Color Health	RCV000166372	SCV000687484	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-16	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 1169 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 an individual affected with advanced cancer (PMID 28873162). In a large international case-control study, this variant was reported in 1/60465 breast cancer cases and 0/53461 controls (OR=1.768, 95%CI 0.059 to 52.713, p-value=1; PMID: 33471991). This variant has been identified in 1/251336 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.
PreventionGenetics, part of Exact Sciences	RCV000413647	SCV000805540	uncertain significance	not provided	2017-10-20	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000413647	SCV004229209	uncertain significance	not provided	2022-12-28	criteria provided, single submitter	clinical testing	Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity (http://gnomad.broadinstitute.org). Computational tools predict that this variant is damaging.
Natera, Inc.	RCV000204598	SCV001457149	uncertain significance	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing