Submissions for variant NM_000051.4(ATM):c.8711A>G (p.Glu2904Gly)

dbSNP: rs786202826

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165842	SCV000216590	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-11-16	criteria provided, single submitter	clinical testing	The p.E2904G variant (also known as c.8711A>G), located in coding exon 59 of the ATM gene, results from an A to G substitution at nucleotide position 8711. The glutamic acid at codon 2904 is replaced by glycine, an amino acid with similar properties. This alteration has been reported homozygous in an individual with classic ataxia telangiectasia phenotype (Gilad S, Hum. Mol. Genet. 1996 Apr; 5(4):433-9). This alteration has also been reported in 1/7657 BRCA1/2-negative Chinese breast cancer patients (Yang Z et al. Breast Cancer Res Treat, 2019 Apr;174:639-647). Introduction of the missense alteration p.E2904G into a cloned ATM ORF resulted in instability of the recombinant protein. The net effect of this mutation on the recombinant protein was similar to that of most A-T mutations, which are null alleles that produce unstable ATM derivatives and leave the cells without any protein product of the ATM gene. Authors proposed that the highly conserved glutamic acid residue at position 2904 may, therefore, be critical for the protein's stability (Ziv Y, Oncogene 1997 Jul; 15(2):159-67). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae	RCV000230822	SCV000283088	likely pathogenic	Ataxia-telangiectasia syndrome	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 2904 of the ATM protein (p.Glu2904Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with ataxia-telangiectasia and/or breast cancer (PMID: 8845835, 28724667). ClinVar contains an entry for this variant (Variation ID: 186276). 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. Experimental studies have shown that this missense change affects ATM function (PMID: 9244351). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000659280	SCV000781080	likely pathogenic	Familial cancer of breast	2016-11-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000165842	SCV000905052	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-04-11	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with glycine at codon 2904 of the ATM protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant results in the loss of stable ATM protein expression and kinase function (PMID: 9244351, 9733514). This variant has been reported in the literature in the homozygous state in an individual affected with ataxia-telangiectasia (PMID: 8845835) and in a BRCA1/2-negative individual affected with breast cancer (PMID: 30607632). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Baylor Genetics	RCV000659280	SCV004207095	likely pathogenic	Familial cancer of breast	2023-09-30	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000659280	SCV004933171	likely pathogenic	Familial cancer of breast	2024-02-05	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 8845835]. Functional studies indicate this variant impacts protein function [PMID: 9733514, 9244351].