11-108321351-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.
The NM_000051.4(ATM):c.6503C>T(p.Ser2168Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000366 in 1,614,086 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. S2168W) has been classified as Uncertain significance.
Frequency
Consequence
NM_000051.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.6503C>T | p.Ser2168Leu | missense_variant | 45/63 | ENST00000675843.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATM | ENST00000675843.1 | c.6503C>T | p.Ser2168Leu | missense_variant | 45/63 | NM_000051.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000789 AC: 12AN: 152128Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000835 AC: 21AN: 251448Hom.: 0 AF XY: 0.0000662 AC XY: 9AN XY: 135892
GnomAD4 exome AF: 0.0000322 AC: 47AN: 1461840Hom.: 0 Cov.: 31 AF XY: 0.0000261 AC XY: 19AN XY: 727220
GnomAD4 genome ? AF: 0.0000788 AC: 12AN: 152246Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74432
ClinVar
Submissions by phenotype
Ataxia-telangiectasia syndrome Uncertain:3Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 30, 2024 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Department of Neurology, Xijing Hospital, Fourth Military Medical University | Mar 01, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | Jul 02, 2018 | - - |
Hereditary cancer-predisposing syndrome Uncertain:2Benign:1
Benign, criteria provided, single submitter | clinical testing | Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | Feb 27, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 11, 2023 | The p.S2168L variant (also known as c.6503C>T), located in coding exon 44 of the ATM gene, results from a C to T substitution at nucleotide position 6503. The serine at codon 2168 is replaced by leucine, an amino acid with dissimilar properties. This variant has been identified in numerous cancer cohorts as well as unaffected control groups across studies (Decker B et al. J. Med. Genet. 2017;54(11):732-741; Momozawa Y et al. Nat Commun, 2018 10;9:4083; Momozawa Y et al. J Natl Cancer Inst, 2020 Apr;112:369-376; Mizukami K et al. EBioMedicine, 2020 Oct;60:103033; Akcay IM et al. Int J Cancer, 2021 Jan;148:285-295). Additionally, in a study of whole-exome sequencing in patients with features of Cowden syndrome (CS) or Bannayan-Riley-Ruvalcaba syndrome (BRRS) and negative PTEN testing, this alteration was identified in 0/87 patients with CS or BRRS and 1/3476 patients from The Cancer Genome Atlas (TCGA) (Yehia L et al. PLoS Genet, 2018 04;14:e1007352). It has also been identified in individuals diagnosed with breast cancer (Haiman CA et al. PLoS Genet, 2013 Mar;9:e1003419; Fostira F et al. Breast Cancer Res. Treat. 2018;169(1):105-113; Xie Y et al. Clin Genet, 2018 Jan;93:41-51; Kwong A et al. J Mol Diagn, 2020 Apr;22:544-554). This alteration has also been reported in conjunction with an ATM frameshift mutation in a patient with unexplained ataxia; phase was not reported (Cheng HL et al. Transl Neurodegener, 2021 Oct;10:40). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious 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 | clinical testing | Color Diagnostics, LLC DBA Color Health | May 31, 2023 | This missense variant replaces serine with leucine at codon 2168 of the ATM protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, 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: 23555315, 28580595, 28779002, 29335925, 30287823, 33471991) and in unaffected individuals (PMID: 30287823, 32658311, 33471991). This variant has also been identified in 24/282838 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 provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 31, 2023 | Observed in individuals with breast, pancreatic or colon cancer, and also in unaffected controls (Haiman et al., 2013; Decker et al., 2017; Fostira et al., 2018; Momozawa et al., 2018; Xie et al., 2018; Yehia et al., 2018; Ackay et al., 2020; Kwong et al., 2020; Mizukami et al., 2020); Observed with a truncating ATM variant in a child with ataxia and dysarthria, and it is not known whether the variants occurred on the same (in cis) allele or on opposite (in trans) alleles (Cheng et al., 2021); In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31248605, 29684080, 32068069, 32658311, 28580595, 23555315, 28779002, 29335925, 30287823, 36300887, 32980694, 23532176, 34663476) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | May 17, 2022 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 02, 2021 | Variant summary: ATM c.6503C>T (p.Ser2168Leu) results in a non-conservative amino acid change located in the PIK-related kinase domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 299890 control chromosomes, predominantly at a frequency of 0.00082 within the East Asian subpopulation in the gnomAD database. The frequency in the East Asian subpopulation is close to, but does not exceed, the estimated maximum allele frequency expected for a pathogenic variant in ATM causing Breast Cancer (0.00082 vs 0.001), allowing no conclusion about variant significance. c.6503C>T has been reported in the literature in individuals affected with Breast and Prostate Cancers (e.g.Haiman_2013, Xie_2018, Fostira_2018, Momozawa_2018, Wei_2019, Kwong_2020). In one large case-control study within the Japanese population, this variant was found in both cases and controls and was not shown to be associated with breast cancer (OR=0.4, p=0.222; Momozawa_2018) . These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. Co-occurrence with another pathogenic variant has been reported (BRCA2 c.5682C>G, p.Y1894X; Wei_2019), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, citing the variant as likely benign (n=1) and uncertain significance (n=6). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. - |
Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at