ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.4362A>C (p.Lys1454Asn) (rs148993589)

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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212012 SCV000149100 uncertain significance not provided 2021-08-02 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with idiopathic perifoveal telangiectasia (Barbazetto 2008); Observed in individuals with breast, endometrial, or colon cancer (Maillet 2002, Broeks 2008, Tavtigian 2009, Lu 2015, Tung 2015, Ring 2016, Decker 2017, Pearlman 2017, Hampel 2018, Hauke 2018); This variant is associated with the following publications: (PMID: 33471991, 18502988, 19781682, 17393301, 12362033, 28779002, 26689913, 27443514, 25186627, 29596542, 27978560, 25759019, 27150160, 10425038, 30197789, 29522266, 25925381, 11505391, 12697903, 22529920)
Ambry Genetics RCV000115191 SCV000186552 benign Hereditary cancer-predisposing syndrome 2015-06-28 criteria provided, single submitter clinical testing In silico models in agreement (benign);Internal frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance;Other strong data supporting benign classification
Invitae RCV001080906 SCV000254104 benign Ataxia-telangiectasia syndrome 2020-12-08 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115191 SCV000682199 likely benign Hereditary cancer-predisposing syndrome 2020-08-12 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000212012 SCV000805560 uncertain significance not provided 2017-07-06 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000212012 SCV000883421 uncertain significance not provided 2017-07-03 criteria provided, single submitter clinical testing The p.Lys1454Asn variant has been reported in individuals with breast cancer (Broeks 2008 Teraoka 2001, Tavtigian 2009), endometrial cancer (Ring 2016), and idiopathic perifoveal telangiectasia (Barbazetto 2008) but has not been reported in association with ataxia telangiectasia. This variant is listed in the genome Aggregation Database (gnomAD) with an overall population frequency of 0.03 percent (identified on 84 out of 276,958 chromosomes) and has been reported to ClinVar (Variation ID: 127386). The lysine at position 1454 is moderately conserved (Alamut v.2.9.0) and computational analyses of the effects of the p.Lys1454Asn variant on protein structure and function predict a neutral effect (SIFT: tolerated, Align GVGC: C0 (benign), PolyPhen-2: benign). Altogether, there is not enough evidence to classify the p.Lys1454Asn variant with certainty.
Athena Diagnostics Inc RCV000212012 SCV001143108 uncertain significance not provided 2020-07-16 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000212012 SCV001148421 uncertain significance not provided 2018-05-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001193007 SCV001361526 likely benign not specified 2021-05-24 criteria provided, single submitter clinical testing Variant summary: ATM c.4362A>C (p.Lys1454Asn) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0003 in 259596 control chromosomes, predominantly at a frequency of 0.0006 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in ATM causing Ataxia-Telangiectasia (0.0003 vs 0.001), allowing no conclusion about variant significance. c.4362A>C has been reported in the literature in individuals undergoing multigene panel testing for a variety of hereditary cancers without strong evidence for causality (e.g. Broeks_2008, Tavtigian_2009, Tung_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Ataxia-Telangiectasia or breast cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (Benign, n=2; VUS, n=8). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the absence of any concrete evidence supporting an actionable outcome in over 4 years of review performed at our laboratory and in the literature as evidence outlined above, the variant was re-classified as likely benign.
Division of Medical Genetics, University of Washington RCV001257478 SCV001434284 uncertain significance Familial cancer of breast 2019-11-25 criteria provided, single submitter clinical testing This variant has been reported in the literature in individuals with breast cancer and in an individual with endometrial cancer (Teraoka 2001, Broeks 2008, Tavtigian 2009, Lu 2015, Ring 2016), as well as in an individual with idiopathic perifoveal telangiectasia (Barbazetto 2008). This variant has an overall allele frequency of 0.0003 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). In silico analyses indicate that this variant does not alter protein structure/function. Thus, it is unknown at this time whether this variant increases cancer risk. BP4
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212012 SCV001469352 uncertain significance not provided 2020-07-16 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000212012 SCV001554023 uncertain significance not provided no assertion criteria provided clinical testing The ATM p.Lys1454Asn variant was identified in 6 of 10774 proband chromosomes (frequency: 0.00056) from individuals or families with breast and colon cancer (Barbazetto_2008, Broeks_2008, Maillet_2002, Pearlman_2016, Tavtigian_2009, Teraoka_2001). The variant was also identified in dbSNP (ID: rs148993589) as “With Uncertain significance allele”, ClinVar (as benign by Ambry Genetics and as uncertain significance by GeneDx, Invitae, and Color Genomics), Clinvitae (as in ClinVar), and in Cosmic. The variant was not identified in the COGR, MutDB, or LOVD 3.0 databases. The variant was identified in control databases in 84 of 276958 chromosomes at a frequency of 0.000303 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 1 of 24022 chromosomes (freq: 0.000042), Other in 1 of 6452 chromosomes (freq: 0.000155), European (Non-Finnish) in 76 of 126554 chromosomes (freq: 0.000601), Ashkenazi Jewish in 3 of 10138 chromosomes (freq: 0.000296), and European (Finnish) in 3 of 25770 chromosomes (freq: 0.000116); it was not observed in the Latino, East Asian, and South Asian populations. The p.Lys1454Asn 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 was identified in a laboratory in one individual with a co-occurring pathogenic BRCA2 variant p.Gln2943ArgfsX33 in a family with HBOC, increasing the likelihood that the p.Lys1454Asn variant does not have clinical significance. 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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000212012 SCV001743788 likely benign not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000212012 SCV001808908 likely benign not provided no assertion criteria provided clinical testing
Clinical Genetics Laboratory, Department of Pathology,Netherlands Cancer Institute RCV000212012 SCV001906040 likely benign not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000212012 SCV001954353 likely benign not provided no assertion criteria provided clinical testing

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