Submissions for variant NM_000051.4(ATM):c.2873A>G (p.Glu958Gly)

dbSNP: rs587778069

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000766496	SCV000209714	uncertain significance	not provided	2023-01-10	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24728327, 29470806, 31159747, 28652578, 33875564, 19781682, 36200007, 32885271)
Ambry Genetics	RCV000159703	SCV000215022	uncertain significance	Hereditary cancer-predisposing syndrome	2024-03-20	criteria provided, single submitter	clinical testing	The p.E958G variant (also known as c.2873A>G), located in coding exon 18 of the ATM gene, results from an A to G substitution at nucleotide position 2873. The glutamic acid at codon 958 is replaced by glycine, an amino acid with similar properties. This alteration has been identified in individuals diagnosed with breast and/or ovarian cancer (Singh J et al. Breast Cancer Res Treat, 2018 Jul;170:189-196; Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). Additionally, this alteration has been reported as variant of uncertain significance in 1/1197 individuals from Greece, Romania, and Turkey undergoing evaluation for inherited cancer predisposition (Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000528438	SCV000622371	likely benign	Ataxia-telangiectasia syndrome	2024-01-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000159703	SCV000682085	likely benign	Hereditary cancer-predisposing syndrome	2020-02-04	criteria provided, single submitter	clinical testing
GeneKor MSA	RCV000159703	SCV000821842	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000528438	SCV001653365	uncertain significance	Ataxia-telangiectasia syndrome	2021-05-18	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000120128	SCV004243426	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing
ITMI	RCV000120128	SCV000084266	not provided	not specified	2013-09-19	no assertion provided	reference population
Natera, Inc.	RCV000528438	SCV001461097	uncertain significance	Ataxia-telangiectasia syndrome	2020-01-04	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355117	SCV001549906	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The ATM p.Glu958Gly variant was identified in 2 of 2020 proband chromosomes (frequency: 0.001) from individuals or families with hereditary breast and ovarian cancer and was present in 1 of 4362 control chromosomes (frequency: 0.0002) from healthy individuals (Bodian 2014, Singh 2017). The variant was also identified in dbSNP (ID: rs587778069) as "With Uncertain Significance allele" and in the ClinVar (5x as Uncertain significance by Invitae, Ambry Genetics, GeneDx and two other submitters) database. The variant was not identified in LOVD 3.0 database. It was identified in control databases in 24 of 246208 chromosomes at a frequency of 0.0001 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Latino in 1 of 33580 chromosomes (freq: 0.00003), European in 1 of 111676 chromosomes (freq: 0.000009), and South Asian in 22 of 30780 chromosomes (freq: 0.0007), while the variant was not observed in the African, Other, Ashkenazi Jewish, East Asian or Finnish populations. The p.Glu958 residue is not 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.