rs786203165
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PP3_Moderate
The NM_000051.4(ATM):āc.7775C>Gā(p.Ser2592Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000304 in 1,613,728 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S2592P) 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 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.7775C>G | p.Ser2592Cys | missense_variant | 52/63 | ENST00000675843.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATM | ENST00000675843.1 | c.7775C>G | p.Ser2592Cys | missense_variant | 52/63 | NM_000051.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152172Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 250918Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135612
GnomAD4 exome AF: 0.0000315 AC: 46AN: 1461556Hom.: 0 Cov.: 31 AF XY: 0.0000330 AC XY: 24AN XY: 727088
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152172Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74334
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Pathogenic:1Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 18, 2024 | The p.S2592C variant (also known as c.7775C>G), located in coding exon 51 of the ATM gene, results from a C to G substitution at nucleotide position 7775. The serine at codon 2592 is replaced by cysteine, an amino acid with dissimilar properties. This alteration has been identified in an individual diagnosed with ataxia telangiectasia; however a second ATM alteration was not documented (Neubauer S et al. Radiat Res, 2002 Mar;157:312-21). This alteration has been reported in 1/4,112 breast cancer cases and 0/2,399 controls in a meta-analysis of the role of the ATM gene in breast cancer susceptibility (Tavtigian SV et al. Am. J. Hum. Genet. 2009 Oct;85:427-46). This variant has also been detected in cohorts of patients with non-Hodgkin lymphoma, multiple primary tumors, and prostate cancer (Sipahimalani P et al. Int. J. Cancer. 2007 Nov;121:1967-75; Abida W et al. JCO Precis Oncol. 2017 Jul;2017; Whitworth J et al. Am. J. Hum. Genet. 2018 Jul;103:3-18; Karlsson Q et al. Eur Urol Oncol, 2021 Aug;4:570-579). In functional studies, this variant demonstrated an absence of kinase activity in vivo and in vitro, and increased sensitivity to ionizing radiation (Scott SP et al. Proc. Natl. Acad. Sci. U.S.A. 2002 Jan;99:925-30). Scott et al. also demonstrated the ability of the p.S2592C variant to interfere with wild-type kinase activity in a dominant negative fashion. 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 | Jan 08, 2024 | This missense variant replaces serine with cysteine at codon 2592 of the ATM protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. A functional study has reported that this variant protein has no detectable kinase activity and fails to rescue the elevated radiosensitivity and chromosome aberration phenotype in ATM-deficient cells (PMID: 11805335). This variant has been observed in individuals affected with breast cancer (PMID: 11606401, 19781682, 26898890, 28779002), prostate cancer (PMID: 28825054), non-Hodgkin lymphoma (PMID: 17640065) and multiple primary tumors (PMID: 29909963) and in an unaffected control in a breast cancer case-control study (PMID: 28779002). In a separate, international case-control meta-analysis, this variant was reported in 4/60466 breast cancer cases and 6/53461 controls (OR=0.589, 95%CI 0.166 to 2.089, p-value=0.531; PMID: 33471991). This variant has been identified in 4/250918 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. - |
Likely pathogenic, flagged submission | research | Academic Department of Medical Genetics, University of Cambridge | Jan 26, 2018 | Application of AMCG guidelines 2015. Used other ClinVar submission evidence where relevant. Loss of heterozygosity in tumours or immunohistochemistry abnormalities considered functional evidence of pathogenicity. - |
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 19, 2022 | Variant summary: ATM c.7775C>G (p.Ser2592Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 250918 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7775C>G has been reported in the literature as a heterozygous carrier genotype in individuals with a variety of cancers such as breast, non-Hodgkin lymphoma (NHL), Multiple primary tumors (MPTs), Prostate Cancer and other ATM-associated tumors (example, Dork_2001, Scott_2002, Bremer_2003, Meyer_2004, Sipahimalni_2007, Whitworth_2018, Karlsson_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Ataxia-Telangiectasia/ATM-related cancers. At least one publication reports experimental evidence evaluating an impact on protein function demonstrating 1. a lack of ATM-kinase activity in vitro, 2. dominantly interfered with ATM kinase activity in wild type cells by preventing activation of endogenous ATM kinase in vitro and in vivo, 3. failed to correct the radiosensitivity and elevated chromosomal abberations in AT1ABR cells, lastly, 4. cells transfected with S2592C showed enhanced sensitivity to radiation similar to that of an AT cell line (Scott_2002). However, the data as presented in this study were not quantified to a residual activity. This study has been widely cited listing this as a "Kinase Dead" (KD) variant of ATM (example, Putti_2021). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 (VUS, n=7; LP, n=1). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, until additional consensus opinions around this variant evolve, the variant was classified as uncertain significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Feb 06, 2024 | - - |
Ataxia-telangiectasia syndrome Uncertain:2
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Jun 08, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 02, 2022 | This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 2592 of the ATM protein (p.Ser2592Cys). This variant is present in population databases (rs755009196, gnomAD 0.004%). This missense change has been observed in individual(s) with breast cancer, prostate cancer, or Non-Hodgkin's lymphoma (PMID: 11606401, 11805335, 17640065, 19781682, 28825054, 29909963). ClinVar contains an entry for this variant (Variation ID: 186713). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects ATM function (PMID: 11805335). 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. - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 20, 2022 | Published functional studies suggest a damaging effect: absent kinase activity, increased radiosensitivity in vitro, and dominant interfering effect (Scott et al., 2002); Reported in individuals with breast or prostate cancer, but also in healthy controls (Dork et al., 2001; Tavtigian et al., 2009; Caminsky et al., 2016; Abida et al., 2017; Decker et al., 2017; Karlsson et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); 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: 19781682, 11606401, 15279808, 14643952, 16652348, 21910157, 12552566, 18568480, 16112413, 11839094, 12810666, 12969974, 21787400, 12511424, 20346647, 15450731, 28825054, 28779002, 28873162, 26898890, 29909963, 27535533, 33436325, 11805335) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | May 28, 2020 | - - |
Familial cancer of breast Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Nov 21, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at