ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.5375T>C (p.Ile1792Thr) (rs776309355)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000206668 SCV000259370 uncertain significance Ataxia-telangiectasia syndrome 2016-12-30 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 1792 of the ATM protein (p.Ile1792Thr). The isoleucine residue is weakly conserved and there is a moderate physicochemical difference between isoleucine and threonine. While this variant is present in population databases (rs776309355), the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with a ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 219484). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). The threonine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000566874 SCV000672618 likely benign Hereditary cancer-predisposing syndrome 2016-01-04 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other strong data supporting benign classification
Color Health, Inc RCV000566874 SCV001343983 uncertain significance Hereditary cancer-predisposing syndrome 2020-01-17 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001354647 SCV001549312 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The ATM p.Ile1792Thr variant was not identified in the literature nor was it identified in LOVD 3.0. The variant was identified in dbSNP (ID: rs776309355) as "With Uncertain significance allele", ClinVar (classified as likely benign by Ambry Genetics; as uncertain significance by Invitae). The variant was identified in control databases in 3 of 276752 chromosomes at a frequency of 0.00001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 1 of 126310 chromosomes (freq: 0.000008), East Asian in 2 of 18862 chromosomes (freq: 0.0001), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, Finnish, and South Asian populations. The p.Ile1792 residue is not conserved in mammals and four out of four computational analyses (PolyPhen-2, SIFT, AlignGVGD, 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 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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.

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