ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.4949A>G (p.Asn1650Ser) (rs55870064)

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000589659 SCV000149109 likely benign not provided 2020-10-09 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 24951259, 19781682, 21787400, 17344846, 24728327, 26976419, 26787654, 26689913, 23555315, 21910157, 12969974, 26506520, 22529920, 20232390, 20305132, 28580595)
Invitae RCV001082738 SCV000166113 benign Ataxia-telangiectasia syndrome 2020-12-04 criteria provided, single submitter clinical testing
Ambry Genetics RCV000115200 SCV000212953 benign Hereditary cancer-predisposing syndrome 2014-11-19 criteria provided, single submitter clinical testing This alteration is classified as 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.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000120142 SCV000334654 benign not specified 2015-08-28 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115200 SCV000682231 benign Hereditary cancer-predisposing syndrome 2015-04-13 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000120142 SCV000694294 likely benign not specified 2020-09-04 criteria provided, single submitter clinical testing Variant summary: ATM c.4949A>G (p.Asn1650Ser) results in a conservative amino acid change in 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 0.0012 in 304304 control chromosomes, predominantly at a frequency of 0.0073 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 7-fold of the estimated maximal expected allele frequency for a pathogenic variant in ATM causing Breast Cancer phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.4949A>G has been reported in the literature in individuals affected with different types of cancer including breast cancer, gastric cancer, pancreatic cancer, biliary tract carcinoma, colorectal cancer and lung cancer (e.g. Tavtigian_2009, Bernstein_2010, Harismendy_2013, Grant_2015, Huang_2015, Lu_2015, Tung_2016, Toh_2018, Xie_2018, Terashima_2019) but it was also reported in a large number of controls (e.g. Shi_2011, Momozawa_2018). These data do not provide unequivocal conclusions about association of the variant with Breast Cancer. Co-occurrences with pathogenic variants have been reported (RAD51D c.904-2A>T; ATM c.5712dupA, p.Ser1905fsX25; Internal testing), providing supporting evidence for a benign role. Experimental evidence evaluating an impact on protein function indicated that the variant is associated with defective ATM activity (Takagi_2004). Eight ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Athena Diagnostics Inc RCV000589659 SCV000840943 likely benign not provided 2020-03-27 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000589659 SCV001249806 likely benign not provided 2021-04-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001082738 SCV001264587 likely benign 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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000589659 SCV001469354 likely benign not provided 2020-03-27 criteria provided, single submitter clinical testing
ITMI RCV000120142 SCV000084282 not provided not specified 2013-09-19 no assertion provided reference population
True Health Diagnostics RCV000115200 SCV000787867 likely benign Hereditary cancer-predisposing syndrome 2017-08-22 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000589659 SCV001551223 likely benign not provided no assertion criteria provided clinical testing The ATM p.Asn1650Ser variant was identified in 63 of 23302 proband chromosomes (frequency: 0.003) from individuals or families with breast or ovarian cancer and was present in 220 of 52,260 control chromosomes (frequency: 0.005) from healthy individuals (Momozawa 2018, Tavtigian 2009, Tung 2016). The variant was identified in dbSNP (rs55870064) as “with uncertain significance, other allele”, ClinVar (classified as benign by Color, Invitae, Ambry Genetics and Eurofins; and as likely benign by GeneDx, Integrated Genetics, Athena Diagnostics and True Health Diagnostics) and LOVD 3.0 (observed 6x). The variant was identified in control databases in 159 of 282,444 chromosomes at a frequency of 0.0006 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: East Asian in 148 of 19,934 chromosomes (freq: 0.007, increasing the likelihood this could be a low frequency benign variant), Other in 3 of 7208 chromosomes (freq: 0.0004), African in 6 of 24,966 chromosomes (freq: 0.0002), Latino in 1 of 35,432 chromosomes (freq: 0.00003), and European in 1 of 128,834 chromosomes (freq: 0.000008); it was not observed in the Ashkenazi Jewish, Finnish or South Asian populations. This variant has been identified by our laboratory in a patient with a co-occurring, pathogenic ATM variant (c.8288del, p.Arg2763Glnfs*43), who was not affected by ataxia telangiectasia, and in another patient with a co-occurring, pathogenic BRCA2 variant (c.4940_4941del, p.Thr1647Serfs*18), decreasing the likelihood that this variant has clinical significance. The p.Asn1650 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 although 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this information is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Clinical Genetics Laboratory, Department of Pathology,Netherlands Cancer Institute RCV000589659 SCV001905770 likely benign not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000589659 SCV001957087 likely benign not provided no assertion criteria provided clinical testing

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