ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.4066A>G (p.Asn1356Asp)

gnomAD frequency: 0.00014  dbSNP: rs147600485
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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000586490 SCV000149094 likely benign not provided 2022-08-04 criteria provided, single submitter clinical testing See Variant Classification Assertion Criteria.
Invitae RCV000122846 SCV000166104 likely benign Ataxia-telangiectasia syndrome 2024-02-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV000115185 SCV000185691 likely benign Hereditary cancer-predisposing syndrome 2018-05-30 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.
Genetic Services Laboratory, University of Chicago RCV000212008 SCV000593502 uncertain significance not specified 2017-02-21 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000212008 SCV000694272 likely benign not specified 2023-05-15 criteria provided, single submitter clinical testing Variant summary: ATM c.4066A>G (p.Asn1356Asp) results in a conservative amino acid change located in the Armadillo-type fold domain of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 248760 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing Breast Cancer (0.00014 vs 0.001), allowing no conclusion about variant significance. c.4066A>G has been reported in the literature as a VUS in settings of multigene panel testing in individuals affected with and/or undergoing testing for various types Cancer (example, Yurgelun_2015, Goldgar_2011, Sommer_2003, Tavtigian_2009, Caminsky_2016, Decker_2017, Lu_2015, Tung_2015, Oleary_20019, Dalmasso_2021, Dorling_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Breast Cancer/Ataxia-Telangiectasia. At-least two co-occurrences with other pathogenic variant(s) have been reported in the literature and at our laboratory (Yurgelun_2015, MSH2 del exons 8-15; Our laboratory, BRCA2 c.5350_5351delAA , p.Asn1784HisfsX2), providing supporting evidence for a benign role. 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: 26898890, 34262154, 28779002, 33471991, 21787400, 26689913, 30938815, 12935922, 19781682, 25186627, 25980754). Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments (Likely benign, n=5; VUS, n=7). Based on the evidence outlined above, the variant was classified as likely benign.
Athena Diagnostics Inc RCV000586490 SCV000840937 uncertain significance not provided 2020-10-26 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000115185 SCV000902670 likely benign Hereditary cancer-predisposing syndrome 2016-02-23 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000586490 SCV001148418 likely benign not provided 2023-10-01 criteria provided, single submitter clinical testing ATM: BP4
Illumina Laboratory Services, Illumina RCV000122846 SCV001262666 uncertain significance Ataxia-telangiectasia syndrome 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000586490 SCV001473120 uncertain significance not provided 2019-12-28 criteria provided, single submitter clinical testing The ATM c.4066A>G; p.Asn1356Asp variant (rs147600485) is reported in the literature in individuals with breast cancer (Sommer 2003, Tavtigian 2009, Tung 2015), and Lynch syndrome (Yurgelun 2015); however, this variant co-occurred with a pathogenic MSH2 deletion of exons 8-15 (Yurgelun 2015). This variant is also reported in ClinVar (Variation ID: 127380). It is found in the general population with an overall allele frequency of 0.01% (39/280160 alleles) in the Genome Aggregation Database. The asparagine at codon 1356 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Due to limited information, the clinical significance of this variant is uncertain at this time. REFERENCES Sommer SS et al. ATM missense mutations are frequent in patients with breast cancer. Cancer Genet Cytogenet. 2003 Sep;145(2):115-20. 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):427-46. Tung N et al. Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel. Cancer. 2015 Jan 1;121(1):25-33. 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.
Mayo Clinic Laboratories, Mayo Clinic RCV000586490 SCV001713575 uncertain significance not provided 2016-05-16 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000586490 SCV002047333 uncertain significance not provided 2023-03-21 criteria provided, single submitter clinical testing In the published literature, this variant has been reported in individuals with breast cancer (PMIDs: 33471991 (2021); LOVD3 Shared (https://databases.lovd.nl/shared/), 30938815 (2019), 28779002 (2017), 26898890 (2016), 19781682 (2009), and 12935922 (2003)), pancreatic cancer (PMID: 35047863 (2022)), and melanoma (PMID: 34262154 (2021)). The variant has also been reported in unaffected individuals (PMIDs: 35047863 (2022), 33471991 (2021); LOVD3 Shared (https://databases.lovd.nl/shared/), 28779002 (2017), 19781682 (2009), and FLOSSIES database (https://whi.color.com/)). In an individual undergoing multigene panel testing for suspected Lynch syndrome, this variant was reported to co-occur with a pathogenic variant in the MSH2 gene (PMID: 25980754 (2015)). The frequency of this variant in the general population, 0.00041 (20/48670 chromosomes in North-Western European subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Sema4, Sema4 RCV000115185 SCV002528963 likely benign Hereditary cancer-predisposing syndrome 2021-06-24 criteria provided, single submitter curation
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV003492457 SCV004240669 uncertain significance Breast and/or ovarian cancer 2022-11-08 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001358328 SCV001554030 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The ATM p.Asn1356Asp variant was identified in 5 of 12902 proband chromosomes (frequency: 0.0004) from individuals or families with breast cancer or Lynch syndrome and was not identified in 7566 control chromosomes from healthy individuals (Sommer 2003, Goldgar 2011, Tavtigian 2009, Yurgelun 2015). The variant was also identified in dbSNP (ID: rs147600485) as "With Uncertain significance allele", ClinVar (classified as likely benign by Ambry Genetics; and as uncertain significance by Invitae, GeneDx and three other submitters). The variant was not identified in LOVD 3.0 database. The variant was identified in control databases in 36 of 274476 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 3 of 24030 chromosomes (freq: 0.0001) and European in 33 of 124140 chromosomes (freq: 0.0003), while the variant was not observed in the Other, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Asn1356 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out 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.
GenomeConnect - Invitae Patient Insights Network RCV001535806 SCV001749980 not provided Familial cancer of breast; Ataxia-telangiectasia syndrome no assertion provided phenotyping only Variant interpreted as Likely benign and reported on 10-31-2019 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.

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