rs56123940
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6
The NM_000051.4(ATM):c.749G>A(p.Arg250Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000576 in 1,613,626 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R250G) has been classified as Uncertain significance.
Frequency
Consequence
NM_000051.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.749G>A | p.Arg250Gln | missense_variant | 7/63 | ENST00000675843.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATM | ENST00000675843.1 | c.749G>A | p.Arg250Gln | missense_variant | 7/63 | NM_000051.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000592 AC: 9AN: 152018Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000478 AC: 12AN: 250992Hom.: 1 AF XY: 0.0000369 AC XY: 5AN XY: 135656
GnomAD4 exome AF: 0.0000575 AC: 84AN: 1461608Hom.: 1 Cov.: 32 AF XY: 0.0000605 AC XY: 44AN XY: 727110
GnomAD4 genome ? AF: 0.0000592 AC: 9AN: 152018Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2AN XY: 74242
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:1Benign:3
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 29, 2018 | 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneKor MSA | Aug 01, 2018 | - - |
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Dec 09, 2020 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Aug 05, 2015 | - - |
not provided Uncertain:1Benign:2Other:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Oct 28, 2020 | This variant is associated with the following publications: (PMID: 19404735, 17344846, 22529920, 28779002, 31159747) - |
not provided, no classification provided | phenotyping only | GenomeConnect, ClinGen | - | Variant interpreted as Uncertain significance and reported on 08-11-2016 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2022 | ATM: BP4, BS2 - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jul 20, 2021 | - - |
Ataxia-telangiectasia syndrome Uncertain:1Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | - - |
Likely benign, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | May 15, 2018 | - - |
Familial cancer of breast Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Division of Medical Genetics, University of Washington | Oct 04, 2019 | This variant has been reported in the literature in an individual with breast cancer (Paglia 2010). This variant has an overall allele frequency of 0.00005 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). In silico analyses indicate that this variant does not alter protein structure/function. Thus, it is unknown at this time whether this variant increases cancer risk. BP4 - |
Likely benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Apr 23, 2024 | 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]. - |
Breast and/or ovarian cancer Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | May 24, 2019 | - - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 17, 2021 | Variant summary: ATM c.749G>A (p.Arg250Gln) 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 4.8e-05 in 250992 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than expected for a pathogenic variant in ATM causing Ataxia-Telangiectasia (4.8e-05 vs 0.004), allowing no conclusion about variant significance. However, the presence of a homozygous occurrence in healthy controls suggests that the variant has a neutral impact. c.749G>A has been reported in the literature in settings of multigene panel testing in individuals affected with various cancer phenotypes without strong evidence for causality (examples-Grennman_2007, LaPaglia_2009, Haiman_2013, Tung_2015, Muller_2015, Tiao_2017, Martin-Moales_2018, Tsaousis_2019, Weitzel_2019, Sandoval_2021). These report(s) 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. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=4; VUS, n=4). Based on the emerging majority consensus among peers and the evidence outlined above, the variant was re-classified as likely benign. - |
Hereditary cancer Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Mendelics | Jan 23, 2024 | - - |
Hereditary breast ovarian cancer syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | National Health Laboratory Service, Universitas Academic Hospital and University of the Free State | Apr 19, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at