Submissions for variant NM_000051.4(ATM):c.6860G>A (p.Gly2287Glu)

dbSNP: rs1800061

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164364	SCV000214999	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-29	criteria provided, single submitter	clinical testing	The p.G2287E variant (also known as c.6860G>A), located in coding exon 46 of the ATM gene, results from a G to A substitution at nucleotide position 6860. The glycine at codon 2287 is replaced by glutamic acid, an amino acid with similar properties. This alteration has been identified in colorectal and breast cancer cohorts (Yurgelun MB et al. J. Clin. Oncol., 2017 Apr;35:1086-1095; Hauke J et al. Cancer Med, 2018 04;7:1349-1358; Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). In one study, this alteration was seen in 1/732 breast cancer patients, 1/189 colorectal cancer patients as well as 2/490 cancer-free elderly controls in a Turkish population (Akcay IM et al. Int J Cancer, 2021 Jan;148:285-295). 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	RCV000234176	SCV000283026	uncertain significance	Ataxia-telangiectasia syndrome	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 2287 of the ATM protein (p.Gly2287Glu). This variant is present in population databases (rs1800061, gnomAD 0.006%). This missense change has been observed in individual(s) with colorectal cancer (PMID: 28135145). ClinVar contains an entry for this variant (Variation ID: 185012). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The glutamic acid amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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.
GeneDx	RCV000485783	SCV000569001	uncertain significance	not provided	2023-08-23	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; Identified in individuals with colorectal, breast, or other cancers (Yurgelun et al., 2017; Hauke et al., 2018; Lu et al., 2015); This variant is associated with the following publications: (PMID: 29522266, 28135145, 19781682, 28338653, 23532176, 11606401, 26689913)
Counsyl	RCV000234176	SCV000799668	uncertain significance	Ataxia-telangiectasia syndrome	2018-04-29	criteria provided, single submitter	clinical testing
Mendelics	RCV000234176	SCV000838582	uncertain significance	Ataxia-telangiectasia syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000164364	SCV000902931	uncertain significance	Hereditary cancer-predisposing syndrome	2022-09-12	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with glutamic acid at codon 2287 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 or colorectal cancer (PMID: 28135145, 28338653, 33471991). This variant has been identified in 6/251222 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.
Illumina Laboratory Services, Illumina	RCV000234176	SCV001260751	uncertain significance	Ataxia-telangiectasia syndrome	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001201232	SCV001372325	uncertain significance	not specified	2020-06-29	criteria provided, single submitter	clinical testing	Variant summary: ATM c.6860G>A (p.Gly2287Glu) results in a non-conservative amino acid change located in the PIK-related kinase, FAT domain (IPR003151) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251222 control chromosomes (genomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.6860G>A has been reported in the literature in individuals affected with kidney renal clear cell carcinoma and colorectal cancer (Lu_2015, Yurelun_2017). These reports do not provide unequivocal conclusions about association of the variant with Ataxia-Telangiectasia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000485783	SCV002010790	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001201232	SCV002066686	uncertain significance	not specified	2020-12-01	criteria provided, single submitter	clinical testing	DNA sequence analysis of the ATM gene demonstrated a sequence change, c.6860G>A, in exon 47 that results in an amino acid change, p.Gly2287Glu. This sequence change has been previously described in a patient with colorectal cancer (PMID: 28135145). This sequence change has been described in the gnomAD database with a low population frequency of 0.0024% (dbSNP rs1800061). The p.Gly2287Glu change affects a moderately conserved amino acid residue located in a domain of the ATM protein that is known to be functional. The p.Gly2287Glu substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Gly2287Glu change remains unknown at this time.
Baylor Genetics	RCV003467292	SCV004209406	uncertain significance	Familial cancer of breast	2023-09-22	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000234176	SCV001458456	uncertain significance	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355759	SCV001550727	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The ATM p.Gly2287Glu variant was identified in 1 of 2116 proband chromosomes (frequency: 0.0005) from individuals or families with colorectal cancer (Yurgelun 2017). The variant was also identified in dbSNP (ID: rs1800061) as "With Uncertain significance allele", ClinVar (classified as uncertain significance by Invitae, Ambry Genetics, GeneDx, and two other submitters). The variant was not identified in LOVD 3.0. The variant was identified in control databases in 7 of 245976 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European population in 7 of 111490 chromosomes (freq: 0.00006), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Gly2287 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of 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.