Total submissions: 11
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV000131419 | SCV000186399 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-05-26 | criteria provided, single submitter | clinical testing | The p.I826L variant (also known as c.2476A>C), located in coding exon 16 of the ATM gene, results from an A to C substitution at nucleotide position 2476. The isoleucine at codon 826 is replaced by leucine, an amino acid with highly similar properties. This variant was detected in 1/122 breast cancer patients with a family history of breast cancer and a hematologic malignancy and was not identified in 186 control samples (Paglia L et al. Breast Cancer Res Treat. 2010 Jan;119:443-52). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
Invitae | RCV000168043 | SCV000218696 | uncertain significance | Ataxia-telangiectasia syndrome | 2024-01-29 | criteria provided, single submitter | clinical testing | This sequence change replaces isoleucine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 826 of the ATM protein (p.Ile826Leu). This variant is present in population databases (rs587782397, gnomAD 0.009%). This missense change has been observed in individual(s) with breast cancer and/or chronic lymphocytic leukemia (PMID: 19404735, 20305132, 21993670, 28652578). ClinVar contains an entry for this variant (Variation ID: 142345). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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. |
Gene |
RCV000484154 | SCV000566330 | uncertain significance | not provided | 2023-08-04 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer, renal cancer, or leukemia, but also in unaffected controls (Paglia et al., 2010; Guarini et al., 2012; Lu et al., 2015; Navrkalova et al., 2016; Decker et al., 2017; Tiao et al., 2017); This variant is associated with the following publications: (PMID: 19404735, 21993670, 27479817, 26689913, 28779002, 28652578, 20305132) |
Counsyl | RCV000168043 | SCV000799988 | uncertain significance | Ataxia-telangiectasia syndrome | 2018-05-16 | criteria provided, single submitter | clinical testing | |
Color Diagnostics, |
RCV000131419 | SCV000910809 | likely benign | Hereditary cancer-predisposing syndrome | 2016-08-06 | criteria provided, single submitter | clinical testing | |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000779790 | SCV000916592 | uncertain significance | not specified | 2021-08-13 | criteria provided, single submitter | clinical testing | Variant summary: ATM c.2476A>C (p.Ile826Leu) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 251692 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in ATM causing Ataxia-Telangiectasia (4e-05 vs 0.004), allowing no conclusion about variant significance. The variant, c.2476A>C, has been reported in the literature in individuals affected with Breast Cancer (Bernstein_2010) and CLL (Guarini_2012, LaPaglia_2009, Tiao_2017). These reports however, do not provide unequivocal conclusions about association of the variant with Ataxia-Telangiectasia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven other ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=6) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. |
Athena Diagnostics Inc | RCV000484154 | SCV001143100 | uncertain significance | not provided | 2020-12-03 | criteria provided, single submitter | clinical testing | |
Institute for Clinical Genetics, |
RCV000484154 | SCV002010840 | uncertain significance | not provided | 2021-11-03 | criteria provided, single submitter | clinical testing | |
MGZ Medical Genetics Center | RCV001762310 | SCV002580576 | uncertain significance | Familial cancer of breast | 2021-12-27 | criteria provided, single submitter | clinical testing | |
Baylor Genetics | RCV001762310 | SCV004203705 | uncertain significance | Familial cancer of breast | 2023-10-30 | criteria provided, single submitter | clinical testing | |
Natera, |
RCV000168043 | SCV001462072 | uncertain significance | Ataxia-telangiectasia syndrome | 2020-09-16 | no assertion criteria provided | clinical testing |