ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.2362A>C (p.Ser788Arg) (rs641252)

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000120120 SCV000149063 benign not specified 2015-05-26 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics RCV000115154 SCV000186229 benign Hereditary cancer-predisposing syndrome 2018-08-30 criteria provided, single submitter clinical testing Co-occurence with mutation in same gene (phase unknown);In silico models in agreement (benign);Subpopulation frequency in support of benign classification
Invitae RCV000167934 SCV000218582 benign Ataxia-telangiectasia syndrome 2020-12-04 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000120120 SCV000226196 benign not specified 2015-01-07 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000120120 SCV000593478 likely benign not specified 2016-11-23 criteria provided, single submitter clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. RCV000115154 SCV000679691 likely benign Hereditary cancer-predisposing syndrome 2017-07-12 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115154 SCV000682049 benign Hereditary cancer-predisposing syndrome 2015-10-23 criteria provided, single submitter clinical testing
Counsyl RCV000167934 SCV000792122 likely benign Ataxia-telangiectasia syndrome 2017-06-16 criteria provided, single submitter clinical testing
Mendelics RCV000167934 SCV001138472 likely benign Ataxia-telangiectasia syndrome 2019-05-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000167934 SCV001262549 likely benign Ataxia-telangiectasia syndrome 2017-04-28 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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Spanish ATM Cancer Susceptibility Variant Interpretation Working Group RCV000115154 SCV001911501 benign Hereditary cancer-predisposing syndrome 2020-06-17 criteria provided, single submitter clinical testing The c.2362A>C p.(Ser788Arg) missense variant has an allele frequency of 0.00944 (0.94%, 223/23,614 alleles) in the African population of the gnomAD v2.1.1 non-cancer dataset. Therefore, this variant meets a stand-alone criterion to be classified as benign (BA1; http://gnomad.broadinstitute.org). Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: BA1 (PMID: 33280026).
ITMI RCV000120120 SCV000084258 not provided not specified 2013-09-19 no assertion provided reference population
True Health Diagnostics RCV000115154 SCV000787851 likely benign Hereditary cancer-predisposing syndrome 2017-10-26 no assertion criteria provided clinical testing
Natera, Inc. RCV000167934 SCV001462065 benign Ataxia-telangiectasia syndrome 2020-09-16 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001355240 SCV001550066 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The ATM p.Ser788Arg variant was identified in 3 of 3974 proband chromosomes (frequency: 0.00075) from individuals or families with Lynch Syndrome, breast cancer and a general healthy ancestrally diverse cohort in a study of germline variation in cancer-susceptibility genes (Bodian 2014, Yurgelun 2015, Ianuzzi 2002). The variant was also identified in dbSNP (ID: rs641252) as “With other allele” and ClinVar (4x as benign by Invitae, EGL Genetics, Color, GeneDx and 6x as likely benign by University of Chicago Genetic services, Institute for Biomarker, Counsyl, True Health Diagnostics) databases. The variant was not identified in GeneInsight-COGR, Cosmic, MutDB or LOVD 3.0, databases. The variant was identified in control databases in 242 of 276996 chromosomes (2 homozygous) at a frequency of 0.00087 increasing the likelihood this could be a low frequency variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 230 of 24034 chromosomes (freq: 0.0095), Other in 2 of 6466 chromosomes (freq: 0.0003), Latino in 8 of 34420 chromosomes (freq: 0.0002), European Non-Finnish in 2 of 126668 chromosomes (freq: 0.000016), while the variant was not observed in the Ashkenazi Jewish, East Asian, European Finnish, or South Asian populations. The p.Ser788Arg residue is not conserved in mammals and four out of five 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 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this 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.

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