rs587782236
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_000051.4(ATM):c.5645G>A(p.Arg1882Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000682 in 1,613,962 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1882P) has been classified as Uncertain significance.
Frequency
Consequence
NM_000051.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.5645G>A | p.Arg1882Gln | missense_variant | 37/63 | ENST00000675843.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATM | ENST00000675843.1 | c.5645G>A | p.Arg1882Gln | missense_variant | 37/63 | NM_000051.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152116Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250786Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135600
GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461728Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7AN XY: 727172
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152234Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74440
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 22, 2022 | The p.R1882Q variant (also known as c.5645G>A), located in coding exon 36 of the ATM gene, results from a G to A substitution at nucleotide position 5645. The arginine at codon 1882 is replaced by glutamine, an amino acid with highly similar properties. This variant was observed in 1/7051 unselected female breast cancer patients and was not observed in 11241 female controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). This variant was also detected in a cohort of 337 high risk hereditary breast and/or ovarian cancer patients who previously tested negative for pathogenic BRCA1/2 variants (Schubert S et al. Int J Cancer, 2019 06;144:2683-2694). This amino acid position is 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. - |
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Jan 23, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jun 02, 2021 | This missense variant replaces arginine with glutamine at codon 1882 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 and/or ovarian cancer (PMID: 25186627, 30287823, 30426508). This variant has been identified in 1/250786 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. - |
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 04, 2020 | Variant summary: ATM c.5645G>A (p.Arg1882Gln) 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-06 in 250786 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5645G>A has been reported in the literature in individuals affected with Breast Cancer (Tung_2015, Momozawa_2018, Schubert_2019). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Ataxia-telangiectasia syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 24, 2023 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1882 of the ATM protein (p.Arg1882Gln). This variant is present in population databases (rs587782236, gnomAD 0.007%). This missense change has been observed in individual(s) with breast cancer (PMID: 25186627, 30287823). ClinVar contains an entry for this variant (Variation ID: 142104). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 30, 2023 | 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 and in unaffected control(s) (Tung et al., 2015; Momozawa et al., 2018; Schubert et al., 2019; Dorling et al., 2021); This variant is associated with the following publications: (PMID: 33471991, 30426508, 25186627, 30287823) - |
Familial cancer of breast Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 31, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at