ClinVar Miner

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

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212012 SCV000149100 uncertain significance not provided 2018-10-16 criteria provided, single submitter clinical testing This variant is denoted ATM c.4362A>C at the cDNA level, p.Lys1454Asn (K1454N) at the protein level, and results in the change of a Lysine to an Asparagine (AAA>AAC). This variant has been observed in individuals with breast, endometrial, or colon cancer (Maillet 2002, Broeks 2008, Lu 2015, Tung 2015, Ring 2016, Decker 2017, Pearlman 2017, Hampel 2018, Hauke 2018), and was reported in 3/987 breast cancer cases but absent among 1021 controls in a breast cancer case-control meta-analysis (Tavtigian 2009). Additionally, ATM Lys1454Asn has been identified in an individual with idiopathic perifoveal telangiectasia (Barbazetto 2008). ATM Lys1454Asn was observed at an allele frequency of 0.06% (76/126,554) in individuals of European ancestry in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether ATM Lys1454Asn is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
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 2019-12-31 criteria provided, single submitter clinical testing
Color RCV000115191 SCV000682199 uncertain significance Hereditary cancer-predisposing syndrome 2020-01-07 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 2018-12-11 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
Integrated Genetics/Laboratory Corporation of America RCV001193007 SCV001361526 uncertain significance not specified 2019-03-21 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 285372 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in ATM causing Breast Cancer (0.0003 vs 0.001), allowing no conclusion about variant significance. This variant was found in multiple patients with breast cancer without strong evidence for causality (Bernstein_2010, Broeks_2008, Tavtigian_2009) and also in controls (Edvardsen_2007). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant five times as uncertain significance and once as benign. Based on the evidence outlined above, the variant was classified as uncertain significance.

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