Submissions for variant NM_000051.4(ATM):c.2095G>C (p.Glu699Gln)

dbSNP: rs1060501539

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000460079	SCV000546679	uncertain significance	Ataxia-telangiectasia syndrome	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 699 of the ATM protein (p.Glu699Gln). This variant is present in population databases (no rsID available, gnomAD 0.01%). This missense change has been observed in individual(s) with endometrial, ovarian, and pancreatic cancer (PMID: 30093976, 35171259). ClinVar contains an entry for this variant (Variation ID: 407468). 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 glutamine 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.
Color Diagnostics, LLC DBA Color Health	RCV000581722	SCV000687353	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-17	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with glutamine at codon 699 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. In a large international case-control study, this variant was reported in 2/60464 breast cancer cases and 0/53461 controls (PMID: 33471991). This variant has been identified in 2/251116 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.
Ambry Genetics	RCV000581722	SCV002730327	uncertain significance	Hereditary cancer-predisposing syndrome	2022-05-24	criteria provided, single submitter	clinical testing	The p.E699Q variant (also known as c.2095G>C), located in coding exon 12 of the ATM gene, results from a G to C substitution at nucleotide position 2095. The glutamic acid at codon 699 is replaced by glutamine, an amino acid with highly similar properties. This alteration was detected in a patient with endometrial and ovarian cancer (Chan GHJ et al. Oncotarget, 2018 Jul;9:30649-30660). This amino acid position is 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.
Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University	RCV003153614	SCV003843839	benign	Ovarian cancer	2022-01-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003470413	SCV004212251	uncertain significance	Familial cancer of breast	2022-06-28	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000460079	SCV002076976	uncertain significance	Ataxia-telangiectasia syndrome	2020-07-14	no assertion criteria provided	clinical testing