ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.4324T>C (p.Tyr1442His) (rs201666889)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000115190 SCV000183990 benign Hereditary cancer-predisposing syndrome 2015-09-11 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Seen in trans with a mutation or in homozygous state in individual without severe disease for that gene,Other strong data supporting benign classification
Athena Diagnostics Inc RCV000586538 SCV000840939 uncertain significance not provided 2017-09-18 criteria provided, single submitter clinical testing
Color RCV000115190 SCV000682195 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-18 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000168302 SCV000745125 uncertain significance Ataxia-telangiectasia syndrome 2017-06-15 criteria provided, single submitter clinical testing
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000168302 SCV000732991 uncertain significance Ataxia-telangiectasia syndrome no assertion criteria provided clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515173 SCV000611361 uncertain significance Familial cancer of breast; Ataxia-telangiectasia syndrome 2017-05-23 criteria provided, single submitter clinical testing
GeneDx RCV000586538 SCV000149099 uncertain significance not provided 2018-07-12 criteria provided, single submitter clinical testing This variant is denoted ATM c.4324T>C at the cDNA level, p.Tyr1442His (Y1442H) at the protein level, and results in the change of a Tyrosine to a Histidine (TAT>CAT). This variant has been reported in multiple individuals with leukemia, breast, and/or ovarian cancer but has also been observed in controls (Broeks 2008, Tavtigian 2009, Knappskog 2012, Lu 2015, Maxwell 2016, Tung 2016, Tiao 2017). ATM Tyr1442His was observed at an allele frequency of 0.06% (76/126,378) 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 a deleterious effect. Based on currently available evidence, it is unclear whether ATM Tyr1442His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Genome Diagnostics Laboratory,VU University Medical Center Amsterdam RCV000168302 SCV000745814 uncertain significance Ataxia-telangiectasia syndrome 2016-09-07 no assertion criteria provided clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000586538 SCV000694275 uncertain significance not provided 2016-12-09 criteria provided, single submitter clinical testing Variant summary: The ATM c.4324T>C variant affects a conserved nucleotide, resulting in amino acid change from Tyr to His. 3/4 in-silico tools predict this variant to be damaging (SNPs&GO not captured due to low reliability index). This variant is found in 51/119398 control chromosomes at a frequency of 0.0004271, which does not exceed maximal expected frequency of a pathogenic ATM allele for breast cancer (0.0005001) or ataxia-telangiectasia (AT; 0.0039528). The variant has been cited mainly in breast cancer patients, but also in at least 1 pancreatic cancer patients from the literature without significant evidence of causality (eg. co-segregation data). In addition, two other clinical laboratories classified this variant as a VUS and one classified it as benign, all without evidence to independently evaluate. Because of the absence of clinical information and the lack of functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available.
Invitae RCV000168302 SCV000218983 uncertain significance Ataxia-telangiectasia syndrome 2018-12-29 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with histidine at codon 1442 of the ATM protein (p.Tyr1442His). The tyrosine residue is highly conserved and there is a moderate physicochemical difference between tyrosine and histidine. This variant is present in population databases (rs201666889, ExAC 0.07%). This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 17393301, 19781682, 22420423, 26976419, 26689913, 27153395). ClinVar contains an entry for this variant (Variation ID: 127385). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
PreventionGenetics RCV000586538 SCV000805559 uncertain significance not provided 2017-07-06 criteria provided, single submitter clinical testing

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