rs199836342
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6
The NM_000051.4(ATM):āc.5063T>Cā(p.Ile1688Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000155 in 1,614,024 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I1688R) 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 -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.5063T>C | p.Ile1688Thr | missense_variant | 34/63 | ENST00000675843.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATM | ENST00000675843.1 | c.5063T>C | p.Ile1688Thr | missense_variant | 34/63 | NM_000051.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152186Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000677 AC: 17AN: 251210Hom.: 0 AF XY: 0.0000663 AC XY: 9AN XY: 135752
GnomAD4 exome AF: 0.0000157 AC: 23AN: 1461720Hom.: 0 Cov.: 31 AF XY: 0.0000179 AC XY: 13AN XY: 727164
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152304Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74466
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:1Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | May 28, 2021 | 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 | curation | Sema4, Sema4 | Feb 02, 2022 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 23, 2021 | - - |
Ataxia-telangiectasia syndrome Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Dec 20, 2023 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
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 | Oct 19, 2022 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 16, 2023 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in both cases and controls in a breast cancer case-control study (Momozawa et al., 2018); This variant is associated with the following publications: (PMID: 34156717, 27121310, 31638252, 33471991, 30287823, 35681111) - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 14, 2019 | Variant summary: ATM c.5063T>C (p.Ile1688Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 298714 control chromosomes (gnomAD and publication data), and was exclusively observed within the East Asian subpopulation at a frequency of 0.00092 in the gnomAD database. This frequency is slightly lower than expected for a pathogenic variant in ATM causing Breast Cancer (0.00092 vs 0.001), however the variant still might represent a benign polymorphism found predominantly in individuals of East Asian origin. Indeed, a large case-control association study, involving unselected breast cancer (BrC) patients and controls of Japanese ancestry, identified the variant in 3/7051 female BrC cases, but also found the variant in 12/11242 healthy female- and 9/12490 healthy male control individuals, based on their findings the authors of this study concluded that the variant is benign (Momozawa 2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and all laboratories classified the variant as uncertain significance; however all of these classifications were performed before the publication of the Momozawa study. Based on the evidence outlined above, the variant was classified as likely benign. - |
Ataxia-telangiectasia syndrome;C0006142:Malignant tumor of breast Other:1
not provided, no classification provided | phenotyping only | GenomeConnect - Invitae Patient Insights Network | - | Variant interpreted as Uncertain significance and reported on 02-10-2020 by Ambry Genetics. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at