ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.7271T>G (p.Val2424Gly) (rs28904921)

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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212060 SCV000149153 pathogenic not provided 2018-12-31 criteria provided, single submitter clinical testing This pathogenic variant is denoted ATM c.7271T>G at the cDNA level, p.Val2424Gly (V2424G) at the protein level, and results in the change of a Valine to a Glycine (GTA>GGA). This variant was observed at an allele frequency of 0.01% (13/126,414) in individuals of European ancestry in large population cohorts (Lek 2016). ATM Val2424Gly is located in the FAT domain (Stracker 2013). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. In large case-control studies, this variant was observed in multiple individuals with breast cancer, but in only one control individual (Southey 2016, Thompson 2016, Decker 2017). In vivo functional studies have shown cells heterozygous for this variant to be radiosensitive and have decreased kinase activity, leading authors to propose a dominant-negative effect in tumor cells (Stewart 2001, Chenevix-Trench 2002, Barone 2009, Mitui 2009, Taylor 2014). ATM Val2424Gly has been shown to segregate with disease in multiple families and has been suggested to confer a higher risk for breast cancer than other published ATM variants, up to a 50-69% lifetime risk (Stankovic 1998, Chenevix-Trench 2002, Bernstein 2006, Goldgar 2011, van Os 2016). In a recent, large, multi-center case-control analysis, this variant was associated with a significantly increased risk for breast cancer (OR = 11.0; 95% CI 1.42 to 85.7) (Southey 2016). Pathogenic variants in ATM may also increase the risk of other cancers including colon, pancreatic, gastric, prostate, and ovarian, but the risks are uncertain at this time (Thompson 2005, Roberts 2012, Helgason 2015, Norquist 2016, Lilyquist 2017, AlDubayan 2018, Hu 2018). Based on currently available evidence, we consider this variant to be pathogenic. The National Comprehensive Cancer Network has management guidelines for individuals with pathogenic variants in ATM (NCCN). Ataxia-telangiectasia (A-T) is an autosomal recessive condition caused by two pathogenic variants (one affecting each allele) in the ATM gene. This multisystem disorder is characterized by progressive neurodegeneration, telangiectasias, immunodeficiency, and increased cancer risks; however, ATM Val2424Gly has been reported in association with an attenuated phenotype (Stankovic 1998, Chun 2004, Simonin 2008, Taylor 2014). If both parents have a pathogenic ATM variant, the risk to have a child with A-T is 25% with each pregnancy.
Ambry Genetics RCV000115244 SCV000172910 pathogenic Hereditary cancer-predisposing syndrome 2018-06-13 criteria provided, single submitter clinical testing In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Deficient protein function in appropriate functional assay(s);Strong segregation with disease (lod >3 = >10 meioses);Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
Invitae RCV000168223 SCV000218891 pathogenic Ataxia-telangiectasia syndrome 2020-01-08 criteria provided, single submitter clinical testing This sequence change replaces valine with glycine at codon 2424 of the ATM protein (p.Val2424Gly). The valine residue is highly conserved and there is a moderate physicochemical difference between valine and glycine. This variant is present in population databases (rs28904921, ExAC 0.005%). This variant has been reported in individuals affected with autosomal recessive ataxia-telangiectasia (PMID: 9463314, 8755918), and has been observed to segregate with disease in two families (PMID: 18575927, 9463314). It has also been reported in numerous individuals affected with breast cancer (PMID: 11830610, 19781682, 16958054, 21787400, 24733792), and an individual with gastric cancer (PMID: 26506520). ClinVar contains an entry for this variant (Variation ID: 3023). In large multi-center case-control and family-based studies, this variant was shown to be strongly associated with breast cancer risk among Caucasian women (OR=8.0-11.0, 95% CI 1.42-85.7, p<0.01) (PMID: 27595995, 21787400). In two smaller case-control studies, the cumulative risk for breast cancer at age 70 years was determined to be 34-69% (PMID: 11830610, 16958054, 17001622). Experimental studies have shown that this missense change disrupts ATM kinase activity (PMID: 11382771, 11830610, 18634022, 19431188). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000168223 SCV000245452 pathogenic Ataxia-telangiectasia syndrome 2014-09-22 criteria provided, single submitter clinical testing This variant has been previously reported as disease-causing and was found twice in our laboratory in affected individuals who carried second pathogenic variants in the gene.
Genetic Services Laboratory,University of Chicago RCV000168223 SCV000246619 pathogenic Ataxia-telangiectasia syndrome 2014-06-27 criteria provided, single submitter clinical testing
Color RCV000115244 SCV000292134 pathogenic Hereditary cancer-predisposing syndrome 2015-03-09 criteria provided, single submitter clinical testing
Counsyl RCV000168223 SCV000486203 likely pathogenic Ataxia-telangiectasia syndrome 2016-05-16 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000168223 SCV000602560 pathogenic Ataxia-telangiectasia syndrome 2019-05-04 criteria provided, single submitter clinical testing The ATM c.7271T>G; p.Val2424Gly variant (rs28904921) is associated with an increased risk for breast and other cancers (Goldgar 2011, Kurian 2014, Stankovic 1998, Tavtigian 2009, Yurgelun 2015). It is also reported in association with autosomal recessive ataxia telangiectasia in both a homozygous state and in a compound heterozygous state with other ATM variants. (McConville 1996, Stankovic 1998). The p.Val2424Gly variant does not alter the abundance of the ATM protein but several studies have shown that it impairs ATM kinase activity and DNA repair (Barone 2009, Mitui 2009, Stankovic 1998). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 3023). It is found in the general population with an overall allele frequency of 0.004% (12/282354 alleles) in the Genome Aggregation Database. The valine at codon 2424 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is considered to be pathogenic. REFERENCES Barone G et al. Modeling ATM mutant proteins from missense changes confirms retained kinase activity. Hum Mutat. 2009 Aug;30(8):1222-1230. Goldgar DE et al. Rare variants in the ATM gene and risk of breast cancer. Breast Cancer Res. 2011 Jul 25;13(4):R73. Kurian AW et al. Clinical evaluation of a multiple-gene sequencing panel for hereditary cancer risk assessment. J Clin Oncol. 2014 Jul 1;32(19):2001-2009. McConville CM et al. Mutations associated with variant phenotypes in ataxia-telangiectasia. Am J Hum Genet. 1996 Aug;59(2):320-30 Mitui M et al. Functional and computational assessment of missense variants in the ataxia-telangiectasia mutated (ATM) gene: mutations with increased cancer risk. Hum Mutat. 2009 Jan;30(1):12-21 Stankovic T et al. ATM mutations and phenotypes in ataxia-telangiectasia families in the British Isles: expression of mutant ATM and the risk of leukemia, lymphoma, and breast cancer. Am J Hum Genet. 1998 Feb;62(2):334-345. Tavtigian SV et al. Rare, evolutionarily unlikely missense substitutions in ATM confer increased risk of breast cancer. Am J Hum Genet. 2009 Oct;85(4):427-446. Yurgelun MB et al. Identification of a Variety of Mutations in Cancer Predisposition Genes in Patients With Suspected Lynch Syndrome. Gastroenterology. 2015 Sep;149(3):604-13.e20.
Fulgent Genetics,Fulgent Genetics RCV000515429 SCV000611166 pathogenic Familial cancer of breast; Ataxia-telangiectasia syndrome 2017-05-18 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000168223 SCV000694344 pathogenic Ataxia-telangiectasia syndrome 2017-06-05 criteria provided, single submitter clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000709707 SCV000839881 pathogenic Familial cancer of breast 2017-04-03 criteria provided, single submitter clinical testing This c.7271T>G (p.Val2424Gly) has previously been reported in compound heterozygous and homozygous patients with ataxia telangiectasia [PMID 8755918, 9463314, 18575927]. Functional assays showed that the variant does not affect the level of ATM protein but does reduce the level of kinase activity [PMID 18634022]. This variant has seen observed at the heterozygous state in at least 24 patients from two cohorts of breast cancer patients [PMID 19781682, 21787400]. Statistical analysis in one cohort estimated the risk factor for breast cancer to be 8.0 for carriers of this variant compared to 4.4 for families carriers of other pathogenic variants. This variant was observed in 3 Europeans (Non Finnish) at the heterozygous state in the ExAC population database ( This variant is highly conserved in mammals. While not validated for clinical use, computer-based algorithms (SIFT and Polyphen-2) predict this p.Val2424Gly change to be deleterious. It is thus interpreted as a pathogenic variant.
OMIM RCV000003159 SCV000023317 pathogenic Ataxia-telangiectasia variant 2006-11-01 no assertion criteria provided literature only
OMIM RCV000003160 SCV000023318 pathogenic T-cell prolymphocytic leukemia 2006-11-01 no assertion criteria provided literature only
OMIM RCV000003161 SCV000023319 risk factor Breast cancer, susceptibility to 2006-11-01 no assertion criteria provided literature only
CSER _CC_NCGL, University of Washington RCV000417259 SCV000503552 pathogenic Neoplasm of the breast 2016-08-01 no assertion criteria provided research Found in a male patient having exome sequencing for an unrelated indication. No known history of breast cancer. Family history of a mother with bilateral breast cancer diagnosed at age 88 and 93.
GenomeConnect, ClinGen RCV000212060 SCV000986703 not provided not provided no assertion provided phenotyping only Variant interpretted as pathogenic and reported on 11/30/2017 by GTR ID Trillium Health Partners. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

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