chr11-108253989-C-T
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6
The NM_000051.4(ATM):c.2074C>T(p.Arg692Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000254 in 1,613,776 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R692H) 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.2074C>T | p.Arg692Cys | missense_variant | 13/63 | ENST00000675843.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATM | ENST00000675843.1 | c.2074C>T | p.Arg692Cys | missense_variant | 13/63 | NM_000051.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 152068Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251328Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135832
GnomAD4 exome AF: 0.0000267 AC: 39AN: 1461708Hom.: 0 Cov.: 31 AF XY: 0.0000220 AC XY: 16AN XY: 727154
GnomAD4 genome AF: 0.0000132 AC: 2AN: 152068Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74272
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 28, 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 | curation | Sema4, Sema4 | Jun 11, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Feb 27, 2023 | This missense variant replaces arginine with cysteine at codon 692 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 cancer (PMID: 26898890, 28779002). In a large international case-control study, this variant was absent in 60466 breast cancer cases and reported in 1/53460 controls (PMID: 33471991). This variant has been identified in 3/251328 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. - |
Familial cancer of breast Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 23, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Mar 07, 2023 | 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]. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 06, 2018 | Variant summary: ATM c.2074C>T (p.Arg692Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.1e-06 in 246110 control chromosomes. This frequency is lower than expected for a pathogenic variant in ATM causing Ataxia-Telangiectasia (8.1e-06 vs 0.004), allowing no conclusion about variant significance. c.2074C>T has been reported in the literature in an individual affected with breast cancer (Caminsky 2016). This report does 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. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 with conflicting classifications, 2 calling it a VUS and 1 calling it a Likely Benign. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Ataxia-telangiectasia syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 692 of the ATM protein (p.Arg692Cys). This variant is present in population databases (rs765965513, gnomAD 0.002%). This missense change has been observed in individual(s) with clinical features of ATM-related conditions (PMID: 26898890, 28652578, 34326862). ClinVar contains an entry for this variant (Variation ID: 184752). 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 cysteine 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. - |
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 | Mar 23, 2023 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 27, 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 controls (Caminsky et al., 2016; Decker et al., 2017; Dorling et al., 2021); This variant is associated with the following publications: (PMID: 26898890, 27499925, 28779002, 28652578, 33471991) - |
Hereditary breast ovarian cancer syndrome Benign:1
Likely benign, criteria provided, single submitter | curation | German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne | Jan 08, 2024 | ATM specific: AGVGD Class0, SIFT: Tolerated, outside of FATKIN-domain, Found in trans with ATM frameshift variant in a 70 year old patient without signs of AT. According to the ACMG standard criteria we chose these criteria: BP4 (supporting benign): BP4 (ClinGen Interpretation Guidelines for ATM Version 1.1: REVEL score <.249), BS2 (strong benign): Found in trans with ATM frameshift variant in a 70 year old patient without signs of AT - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at