Total submissions: 20
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000590158 | SCV000149072 | uncertain significance | not provided | 2024-06-18 | criteria provided, single submitter | clinical testing | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28202063, 17344846, 28211887, 27978560, 28873162, 28878254, 30303537, 31432501, 33471991, 22529920, 33436325, 32658311, 31742824, 32832836, 31206626, 29522266, 23960188, 20305132, 36029002, 34284872, 36243179) |
Ambry Genetics | RCV000115163 | SCV000185861 | uncertain significance | Hereditary cancer-predisposing syndrome | 2024-09-30 | criteria provided, single submitter | clinical testing | The p.R924W variant (also known as c.2770C>T), located in coding exon 17 of the ATM gene, results from a C to T substitution at nucleotide position 2770. The arginine at codon 924 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been reported in individuals diagnosed with lymphoma, breast cancer, colorectal cancer and pancreatic cancer (de Miranda NF et al. J. Exp. Med. 2013 Aug;210:1729-42; Jalkh N et al. BMC Med Genomics. 2017 Feb;10:8; Pearlman R et al. JAMA Oncol. 2017 Apr;3:464-471; Schwartz M et al. Clin Genet, 2019 12;96:579-584; Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43; Akcay IM et al. Int J Cancer, 2021 01;148:285-295). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. |
Labcorp Genetics |
RCV000232085 | SCV000282911 | uncertain significance | Ataxia-telangiectasia syndrome | 2022-11-01 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 924 of the ATM protein (p.Arg924Trp). This variant is present in population databases (rs55723361, gnomAD 0.06%). This missense change has been observed in individual(s) with breast cancer, colon cancer, diffuse large B-cell lymphoma, and/or ovarian cancer (PMID: 20305132, 27978560, 28202063, 28211887, 29522266, 30303537, 31742824, 32658311). ClinVar contains an entry for this variant (Variation ID: 127358). 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. 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. |
Color Diagnostics, |
RCV000115163 | SCV000682075 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-11-07 | criteria provided, single submitter | clinical testing | This missense variant replaces arginine with tryptophan at codon 924 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 20305132, 28202063, 29522266, 30303537, 32658311, 33471991), pancreatic cancer (PMID: 31432501) and colorectal cancer (PMID: 27978560), but also in unaffected control individuals (PMID: 30303537, 31206626, 33436325, 33471991). In a large international case-control study, this variant was reported in 6/60460 breast cancer cases and 5/53456 controls (OR=1.061, 95%CI 0.324 to 3.477, p-value=1; PMID: 33471991). This variant has been identified in 16/282842 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV001549271 | SCV000694234 | uncertain significance | not specified | 2024-08-22 | criteria provided, single submitter | clinical testing | Variant summary: ATM c.2770C>T (p.Arg924Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3e-05 in 1613908 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing Breast Cancer (3e-05 vs 0.001), allowing no conclusion about variant significance. c.2770C>T has been reported in the literature in settings of multigene panel testing of individuals affected with cancer, however without strong evidence for pathogenicity in multiple cancer types (e.g., Greenman_Nature_2007; Jalkh_BMC Med Genom_2017; Bernstein_JNCI_2010, Girard_2019, etc). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer or Ataxia Telangiectasia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 32658311, 20305132, 22529920, 30303537, 17344846, 28202063, 33436325, 28282032, 27978560, 31432501, 31742824, 31206626, 23960188, 36243179). ClinVar contains an entry for this variant (Variation ID: 127358). Based on the evidence outlined above, the variant was classified as uncertain significance. |
Counsyl | RCV000232085 | SCV000795286 | uncertain significance | Ataxia-telangiectasia syndrome | 2017-11-02 | criteria provided, single submitter | clinical testing | |
Mendelics | RCV000232085 | SCV000838510 | uncertain significance | Ataxia-telangiectasia syndrome | 2018-07-02 | criteria provided, single submitter | clinical testing | |
Fulgent Genetics, |
RCV000763692 | SCV000894572 | uncertain significance | Familial cancer of breast; Ataxia-telangiectasia syndrome | 2021-11-09 | criteria provided, single submitter | clinical testing | |
ARUP Laboratories, |
RCV000590158 | SCV001472199 | uncertain significance | not provided | 2019-09-17 | criteria provided, single submitter | clinical testing | The ATM c.2770C>T; p.Arg924Trp variant (rs55723361) is reported in the literature in individuals affected with breast and colon cancers (Bernstein 2010, Jalkh 2017, Pearlman 2017) and diffuse large B-cell lymphoma (de Miranda 2013, Leeksma 2017), but also in control individuals (Leeksma 2017). This variant is reported in ClinVar (Variation ID: 127358), and is found in the general population with an overall allele frequency of 0.0057% (16/282842 alleles) in the Genome Aggregation Database. The arginine at codon 924 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Due to limited information, the clinical significance of the p.Arg924Trp variant is uncertain at this time. References: Bernstein JL et al. Radiation exposure, the ATM Gene, and contralateral breast cancer in the women's environmental cancer and radiation epidemiology study. J Natl Cancer Inst. 2010 Apr 7;102(7):475-83. de Miranda NF et al. DNA repair genes are selectively mutated in diffuse large B cell lymphomas. J Exp Med. 2013 Aug 26;210(9):1729-42. Jalkh N et al. Next-generation sequencing in familial breast cancer patients from Lebanon. BMC Med Genomics. 2017 Feb 15;10(1):8. Leeksma OC et al. Germline mutations predisposing to diffuse large B-cell lymphoma. Blood Cancer J. 2017 Mar 10;7(3):e541. Pearlman R et al. Prevalence and Spectrum of Germline Cancer Susceptibility Gene Mutations Among Patients With Early-Onset Colorectal Cancer. JAMA Oncol. 2017 Apr 1;3(4):464-471. |
Sema4, |
RCV000115163 | SCV002532808 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-02-09 | criteria provided, single submitter | curation | |
MGZ Medical Genetics Center | RCV002288589 | SCV002580129 | uncertain significance | Familial cancer of breast | 2022-07-25 | criteria provided, single submitter | clinical testing | |
Baylor Genetics | RCV002288589 | SCV004207101 | uncertain significance | Familial cancer of breast | 2024-03-17 | criteria provided, single submitter | clinical testing | |
Athena Diagnostics | RCV000590158 | SCV004229195 | uncertain significance | not provided | 2022-10-15 | criteria provided, single submitter | clinical testing | Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is higher than would generally be expected for pathogenic variants in this gene (http://gnomad.broadinstitute.org). Computational tools disagree on the variant's effect on normal protein function. |
Myriad Genetics, |
RCV002288589 | SCV005084551 | likely benign | Familial cancer of breast | 2024-05-10 | criteria provided, single submitter | clinical testing | This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. |
KCCC/NGS Laboratory, |
RCV002288589 | SCV005089944 | uncertain significance | Familial cancer of breast | 2024-07-31 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 924 of the ATM protein (p.Arg924Trp). This variant is present in population databases (rs55723361, gnomAD 0.06%). This missense change has been observed in individual(s) with breast cancer, colon cancer, diffuse large B-cell lymphoma, and/or ovarian cancer (PMID: 20305132, 27978560, 28202063, 28211887, 29522266, 30303537, 31742824, 32658311). ClinVar contains an entry for this variant (Variation ID: 127358). In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28202063, 17344846, 28211887, 27978560, 28873162, 28878254, 30303537, 31432501, 33471991, 22529920, 33436325, 32658311, 31742824, 32832836, 31206626, 29522266, 23960188, 20305132, 36029002, 34284872, 36243179). 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. |
Natera, |
RCV000232085 | SCV001461094 | uncertain significance | Ataxia-telangiectasia syndrome | 2020-01-10 | no assertion criteria provided | clinical testing | |
Diagnostic Laboratory, |
RCV000590158 | SCV001739762 | uncertain significance | not provided | no assertion criteria provided | clinical testing | ||
Clinical Genetics Laboratory, |
RCV000590158 | SCV001906029 | uncertain significance | not provided | no assertion criteria provided | clinical testing | ||
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, |
RCV000590158 | SCV001956979 | uncertain significance | not provided | no assertion criteria provided | clinical testing | ||
Prevention |
RCV004739388 | SCV005351322 | uncertain significance | ATM-related disorder | 2024-08-16 | no assertion criteria provided | clinical testing | The ATM c.2770C>T variant is predicted to result in the amino acid substitution p.Arg924Trp. This variant has been reported in individuals with breast cancer (Bernstein et al. 2010. PubMed ID: 20305132, Table S2; Jalkh et al. 2017. PubMed ID: 28202063, Table 2; Girard et al. 2018. PubMed ID: 30303537, Table S3), an individual with renal cancer (Greenman et al. 2007. PubMed ID: 17344846, Table S4), individuals with diffuse large B cell lymphoma (de Miranda et al. 2013. PubMed ID: 23960188, Table S3; Leeksma et al. 2017. PubMed ID: 28211887, Table 1), an individual with colorectal cancer (Pearlman et al. 2017. PubMed ID: 27978560, eTable 2), and an individual with familial pancreatic ductal adenocarcinoma (Schwartz et al. 2019. PubMed ID: 31432501, Table 1). It has also been reported in a control individual from a breast cancer cohort study (Girard et al. 2018. PubMed ID: 30303537, Table S3). This variant is reported in 0.058% of alleles in individuals of Ashkenazi Jewish descent in gnomAD and is interpreted as uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/127358/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. |