rs556778314
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PP3_StrongBP6
The NM_000051.4(ATM):c.6975G>A(p.Ala2325=) variant causes a splice region, synonymous change. The variant allele was found at a frequency of 0.0000359 in 1,613,700 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A2325A) has been classified as Uncertain significance.
Frequency
Consequence
NM_000051.4 splice_region, synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.6975G>A | p.Ala2325= | splice_region_variant, synonymous_variant | 47/63 | ENST00000675843.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATM | ENST00000675843.1 | c.6975G>A | p.Ala2325= | splice_region_variant, synonymous_variant | 47/63 | NM_000051.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000527 AC: 8AN: 151776Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251310Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135824
GnomAD4 exome AF: 0.0000342 AC: 50AN: 1461808Hom.: 0 Cov.: 32 AF XY: 0.0000344 AC XY: 25AN XY: 727206
GnomAD4 genome ? AF: 0.0000527 AC: 8AN: 151892Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74224
ClinVar
Submissions by phenotype
not provided Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Dec 27, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 05, 2023 | 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) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Dec 27, 2019 | 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 01, 2017 | - - |
Ataxia-telangiectasia syndrome Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | Dec 29, 2023 | 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. - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 28, 2024 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Feb 17, 2023 | 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. - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 11, 2019 | 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. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 08, 2022 | 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. - |
Familial cancer of breast Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Jul 13, 2021 | ACMG classification criteria: PP3 supporting - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at