chr11-108227661-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.
The NM_000051.4(ATM):c.37C>T(p.Arg13Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000112 in 1,613,346 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. R13G) 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.37C>T | p.Arg13Cys | missense_variant | 2/63 | ENST00000675843.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATM | ENST00000675843.1 | c.37C>T | p.Arg13Cys | missense_variant | 2/63 | NM_000051.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000132 AC: 2AN: 151778Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251386Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135868
GnomAD4 exome AF: 0.0000109 AC: 16AN: 1461568Hom.: 0 Cov.: 30 AF XY: 0.0000124 AC XY: 9AN XY: 727096
GnomAD4 genome ? AF: 0.0000132 AC: 2AN: 151778Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74044
ClinVar
Submissions by phenotype
Ataxia-telangiectasia syndrome Uncertain:3
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 28, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Jun 08, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 21, 2024 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 13 of the ATM protein (p.Arg13Cys). This variant is present in population databases (rs141586345, gnomAD 0.02%). This missense change has been observed in individual(s) with breast cancer (PMID: 10677309, 17393301, 19781682). ClinVar contains an entry for this variant (Variation ID: 185977). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ATM protein function with a negative predictive value of 95%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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. - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 11, 2023 | This missense variant replaces arginine with cysteine at codon 13 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. The variant has been observed in individuals affected with breast cancer (PMID: 17393301, 19781682, 33471991), in an individual with personal or family history of pancreatic cancer (PMID: 29667044), and in multiple unaffected individuals (PMID: 30287823, 33471991). This variant has been identified in 5/251386 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 14, 2022 | The p.R13C variant (also known as c.37C>T), located in coding exon 1 of the ATM gene, results from a C to T substitution at nucleotide position 37. The arginine at codon 13 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been identified in multiple breast cancer cohorts, as well as, in controls (Broeks A et al. Breast Cancer Res Treat. 2008 Jan;107(2):243-8; Momozawa Y et al. Nat Commun. 2018 10;9:4083; Abdel-Razeq H et al. Front Oncol, 2022 Mar;12:673094). This alteration has also been reported with a carrier frequency of 0.00065 in 7,636 unselected prostate cancer patients and 0.00008 in 12,366 male controls of Japanese ancestry (Momozawa Y et al. J Natl Cancer Inst, 2020 04;112:369-376). Additionally, this alteration was reported in a cohort of patients diagnosed with pancreatic ductal adenocarcinoma (Ohmoto A et al. J Gastroenterol. 2018 Oct;53:1159-1167). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 10, 2020 | Variant summary: ATM c.37C>T (p.Arg13Cys) results in a non-conservative amino acid change located in the Telomere-length maintenance and DNA damage repair domain (IPR021668) of 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 2.6e-05 in 303338 control chromosomes (gnomAD and publications). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.37C>T has been reported in the literature in individuals affected with breast cancer, pancreatic ductal adenocarcinoma and chronic lymphocytic leukemia (Ohmoto_2018, te Raa_2015, Tavtigian_2009, Broeks_2008). These reports however, 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. Five other ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 30, 2018 | This variant is denoted ATM c.37C>T at the cDNA level, p.Arg13Cys (R13C) at the protein level, and results in the change of an Arginine to a Cysteine (CGT>TGT). This variant has been observed in at least two women with breast cancer (Broeks 2000, Broeks 2008, Tavtigian 2009). ATM Arg13Cys was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether ATM Arg13Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. - |
Familial cancer of breast Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 17, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at