Submissions for variant NM_000051.4(ATM):c.1010G>A (p.Arg337His)

gnomAD frequency: 0.00006  dbSNP: rs202160435

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000211955	SCV000149040	uncertain significance	not provided	2023-03-30	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast, prostate and other cancers, but also in unaffected controls (Tung et al., 2015; Zhang et al., 2015; Decker et al., 2017; Tiao et al., 2017; Hauke et al., 2018; Girard et al., 2019; Karlsson et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22484628, 29522266, 25078331, 23103869, 27586204, 22037554, 23788652, 24997986, 27067779, 28480077, 24356096, 28179590, 25186627, 28779002, 30303537, 30814645, 32183301, 33436325, 35047863, 33646313, 25882375, 19781682, 36361687, 26580448, 34921020, 35264596, 33415580, 28652578, 20305132)
Ambry Genetics	RCV000115131	SCV000187478	likely benign	Hereditary cancer-predisposing syndrome	2019-04-26	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Invitae	RCV000204640	SCV000260740	benign	Ataxia-telangiectasia syndrome	2024-01-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115131	SCV000681944	uncertain significance	Hereditary cancer-predisposing syndrome	2024-01-04	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 337 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 20305132, 23555315, 25186627, 29522266, 30303537, 33471991) or prostate cancer (PMID: 33436325), but also in control individuals (PMID: 23555315, 30303537, 33471991). This variant has been identified in 20/251160 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.
Mendelics	RCV000204640	SCV000838479	uncertain significance	Ataxia-telangiectasia syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001174655	SCV001337870	uncertain significance	not specified	2023-05-08	criteria provided, single submitter	clinical testing	Variant summary: ATM c.1010G>A (p.Arg337His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.5e-05 in 271398 control chromosomes (gnomAD and publications). This frequency is not higher than the estimated maximum expected for a pathogenic variant in ATM causing Breast Cancer (0.001), allowing no conclusion about variant significance. c.1010G>A has been reported in the literature in individuals affected with Breast Cancer and other tumor phenotypes, including prostate cancer and pediatric retinoblastoma (e.g. Bernstein_2010, Zhang_2015, Tung_2015, Decker_2017, Hauke_2018, Girard_2019, Karlsson_2021, Dorling_2021), but was also found in healthy controls (e.g. Tiao_2017, Girard_2019, Dorling_2021, and in three women older than 70 years of age who have never had cancer, in the FLOSSIES database). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25882375, 24356096, 20305132, 28779002, 22529920, 30303537, 29522266, 30814645, 28652578, 25186627, 26580448, 33436325, 33471991). Ten other submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, mostly without evidence for independent evaluation, and classified the variant as VUS (n=7), likely benign (n=2) or benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Division of Medical Genetics, University of Washington	RCV001257472	SCV001434278	uncertain significance	Familial cancer of breast	2019-10-08	criteria provided, single submitter	clinical testing	This variant has been reported in the literature in individuals with breast cancer (Tung 2015, Decker 2017, Hauke 2018). This variant has an overall allele frequency of 0.00008 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). In silico analyses indicate this is an evolutionarily conserved residue. PP3
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000211955	SCV002010850	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000211955	SCV002497169	likely benign	not provided	2024-01-01	criteria provided, single submitter	clinical testing	ATM: PM2, PM5, BP1, BS2
Sema4, Sema4	RCV000115131	SCV002529641	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-14	criteria provided, single submitter	curation
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV001257472	SCV003843160	uncertain significance	Familial cancer of breast	2022-11-17	criteria provided, single submitter	clinical testing	The ATM c.1010G>A (p.Arg337His) missense change has a maximum subpopulation frequency of 0.012% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. This variant has been reported in individuals with breast and/or cancer (PMID: 30303537, 33646313) and in individuals with prostate cancer (PMID: 33436325) and pancreatic cancer (PMID: 35047863). This variant is present in three individuals in a database of women older than 70 years of age who have never had cancer (FLOSSIES database, https://whi.color.com/). To our knowledge, this variant has not been reported in individuals with ataxia telangiectasia. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001174655	SCV004027144	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000211955	SCV004219895	uncertain significance	not provided	2017-08-21	criteria provided, single submitter	clinical testing	The ATM c.1010G>A (p.Arg337His) variant has been reported in the published literature in individuals with breast cancer (PMID: 33646313 (2021), 25186627 (2015), 28779002 (2017), 29522266 (2018), 30303537 (2019)), prostate cancer (PMID: 33436325 (2021)), chronic lymphocytic leukemia (PMID: 28652578 (2017)), and retinoblastoma (PMID: 26580448 (2015)). In a large-scale breast cancer association study, the variant was observed in individuals with breast cancer as well as in healthy individuals (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/ATM)). In a functional study, fibroblasts homozygous for this variant had normal radiation sensitivity (PMID: 30425284 (2018)), however, further studies are required to determine the global effect of this variant on ATM protein function. The frequency of this variant in the general population, 0.00012 (14/113538 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492451	SCV004240258	uncertain significance	Breast and/or ovarian cancer	2022-12-30	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354564	SCV001549211	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The ATM p.Arg337His variant was not identified in the literature nor was it identified in the COGR, MutDB, LOVD 3.0, and ATM-LOVD databases or the NHLBI GO Exome Sequencing Project. The variant was identified in dbSNP (ID: rs202160435) as “With Uncertain significance allele”, in ClinVar and Clivitae databases with uncertain significance by GeneDx, Ambry Genetics and Invitae); in the Cosmic database 12X in bladder, colon, rectal, gallbladder and stomach carcinomas. The variant was also identified in the 1000 Genomes Project in 2 of 5000 chromosomes (frequency: 0.0004). The variant was identified in control databases in 19 of 245972 chromosomes at a frequency of 0.000077 in the following populations: African in 1 of 15292chromosomes (freq. 0.00007), Latino in 2 of 33536 chromosomes (freq. 0.00006), European Non-Finnish in 15 of 111508 chromosomes (freq. 0.0001), South Asian in 1 of 30782 chromosomes (freq. 0.00003), but was not seen in Ashkenazi Jewish, East Asian, European Finnish and Other populations, increasing the likelihood that this may be a low frequency variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017). The p.Arg337His residue is conserved in mammals but not in more distantly related organisms 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, HumanSpliceFinder) do not predict a difference in splicing. The variant is located with the Armadillo-type fold functional domain. 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.
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000211955	SCV001906136	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000211955	SCV001951035	uncertain significance	not provided		no assertion criteria provided	clinical testing