Total submissions: 10
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV000130288 | SCV000185135 | likely benign | Hereditary cancer-predisposing syndrome | 2019-10-11 | criteria provided, single submitter | clinical testing | This alteration is classified as likely benign based on a combination of the following: 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. |
Invitae | RCV000196388 | SCV000254137 | likely benign | Ataxia-telangiectasia syndrome | 2024-01-28 | criteria provided, single submitter | clinical testing | |
Gene |
RCV000679141 | SCV000292477 | uncertain significance | not provided | 2023-07-05 | criteria provided, single submitter | clinical testing | Observed in individuals with personal and/or family history of breast cancer, but also in unaffected controls (Decker et al., 2017; Gomes et al., 2021; Abdel-Razeq et al., 2022; Guindalini et al., 2022); Not observed at significant frequency in large population cohorts (gnomAD); Alters the last nucleotide of the exon and is predicted to destroy the splice donor site and result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown; Located in the critical FAT domain (Stracker et al., 2013); This variant is associated with the following publications: (PMID: 27149842, 28779002, 33128190, 23532176, 35264596, 35402282) |
Color Diagnostics, |
RCV000130288 | SCV000537558 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-02-17 | criteria provided, single submitter | clinical testing | This synonymous variant alters the conserved G at the last nucleotide position of exon 47 of the ATM gene. Splice site prediction tools suggest this variant may have a significant impact on splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with breast cancer and in healthy controls (PMID: 28779002, 33128190, 35264596, 35402282). This variant has been identified in 3/251310 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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. |
Prevention |
RCV000679141 | SCV000805610 | uncertain significance | not provided | 2017-09-01 | criteria provided, single submitter | clinical testing | |
Athena Diagnostics Inc | RCV000679141 | SCV001475568 | uncertain significance | not provided | 2019-12-27 | criteria provided, single submitter | clinical testing | |
Laboratorio de Genetica e Diagnostico Molecular, |
RCV002243794 | SCV002512252 | uncertain significance | Familial cancer of breast | 2021-07-13 | criteria provided, single submitter | clinical testing | ACMG classification criteria: PP3 supporting |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV002469019 | SCV002766122 | uncertain significance | not specified | 2022-11-08 | criteria provided, single submitter | clinical testing | Variant summary: ATM c.6975G>A (p.Ala2325Ala) alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. One computational tool predicts the variant abolishes a canonical 5' splicing donor site, and three predict the variant has no significant impact on splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.2e-05 in 251310 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.6975G>A has been reported in the literature in individuals affected with breast cancer (Gomes_2020, Abdel-Razeq_2022, Guindalini_2022). These reports 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. Eight ClinVar submitters have assessed the variant since 2014: two classified the variant as likely benign, five as uncertain significance, and one as likely pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance. |
Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000679141 | SCV002774759 | uncertain significance | not provided | 2019-12-27 | criteria provided, single submitter | clinical testing | In the published literature, this variant has been reported in individuals affected with breast cancer (PMIDs: 28779002 (2017), 33128190 (2021), 35264596 (2022), 35402282 (2022)) and unaffected controls (PMID: 28779002 (2017)). The frequency of this variant in the general population, 0.00039 (6/15234 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on ATM mRNA splicing yielded inconclusive findings . Based on the available information, we are unable to determine the clinical significance of this variant. |
Mendelics | RCV000196388 | SCV004176782 | uncertain significance | Ataxia-telangiectasia syndrome | 2023-12-29 | criteria provided, single submitter | clinical testing | This ATM synonymous variant is located at a splice site, with a SpliceAI score of 0.85. In an internal analysis of 6362 Breast Cancer patients and 9128 controls, we found 15 carriers in cases and 10 in controls, yielding an odds-ratio of 2.2, p-value 0.054. |