Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000534505 | SCV000622799 | uncertain significance | Ataxia-telangiectasia syndrome | 2024-10-07 | criteria provided, single submitter | clinical testing | This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 2683 of the ATM protein (p.Ile2683Val). This variant is present in population databases (no rsID available, gnomAD 0.002%). This missense change has been observed in individual(s) with breast cancer (PMID: 28779002). ClinVar contains an entry for this variant (Variation ID: 453719). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt ATM protein function with a negative predictive value of 95%. 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. |
| Ambry Genetics | RCV000565189 | SCV000665476 | likely benign | Hereditary cancer-predisposing syndrome | 2024-06-06 | criteria provided, single submitter | clinical testing | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. |
| Natera, |
RCV000534505 | SCV001452137 | uncertain significance | Ataxia-telangiectasia syndrome | 2020-04-18 | no assertion criteria provided | clinical testing | |
| Department of Pathology and Laboratory Medicine, |
RCV001355951 | SCV001550983 | uncertain significance | Malignant tumor of breast | no assertion criteria provided | clinical testing | The ATM p.Ile2683Val variant was not identified in the literature nor was it identified in the dbSNP, GeneInsight-COGR, Cosmic, MutDB, LOVD 3.0, databases. The variant was identified in ClinVar and Clinvitae (2x as uncertain significance by Invitae, Ambry Genetics). The variant was identified in control databases in 2 of 246040 chromosomes at a frequency of 0.000008 (Genome Aggregation Database Feb 27, 2017). The variant was identified in the European Non-Finnish population in 2 of 111544 chromosomes (freq: 0.00002), while the variant was not observed in the African, “Other”, Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Ile2683 residue is conserved in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; 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, HumanSpliceFinder) 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. |