rs202160435
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM5BP4BP6
The NM_000051.4(ATM):c.1010G>A(p.Arg337His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000744 in 1,613,880 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R337C) has been classified as Uncertain significance.
Frequency
Consequence
NM_000051.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
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.1010G>A | p.Arg337His | missense_variant | 8/63 | ENST00000675843.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATM | ENST00000675843.1 | c.1010G>A | p.Arg337His | missense_variant | 8/63 | NM_000051.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000723 AC: 11AN: 152176Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000796 AC: 20AN: 251160Hom.: 0 AF XY: 0.0000884 AC XY: 12AN XY: 135764
GnomAD4 exome AF: 0.0000746 AC: 109AN: 1461586Hom.: 0 Cov.: 31 AF XY: 0.0000770 AC XY: 56AN XY: 727088
GnomAD4 genome ? AF: 0.0000722 AC: 11AN: 152294Hom.: 0 Cov.: 33 AF XY: 0.0000537 AC XY: 4AN XY: 74470
ClinVar
Submissions by phenotype
not provided Uncertain:5Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2024 | ATM: PM2, PM5, BP1, BS2 - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Aug 21, 2017 | The ATM c.1010G>A (p.Arg337His) variant has been reported in the published literature in individuals with breast cancer (PMID: 33646313 (2021), 25186627 (2015), 28779002 (2017), 29522266 (2018), 30303537 (2019)), prostate cancer (PMID: 33436325 (2021)), chronic lymphocytic leukemia (PMID: 28652578 (2017)), and retinoblastoma (PMID: 26580448 (2015)). In a large-scale breast cancer association study, the variant was observed in individuals with breast cancer as well as in healthy individuals (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/ATM)). In a functional study, fibroblasts homozygous for this variant had normal radiation sensitivity (PMID: 30425284 (2018)), however, further studies are required to determine the global effect of this variant on ATM protein function. The frequency of this variant in the general population, 0.00012 (14/113538 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 11, 2023 | Observed in individuals with breast, prostate and other cancers, and also in unaffected controls (PMID: 25186627, 26580448, 28779002, 28652578, 29522266, 30303537, 33436325); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22484628, 29522266, 25078331, 23103869, 27586204, 22037554, 23788652, 24997986, 27067779, 28480077, 24356096, 28179590, 25186627, 28779002, 30303537, 30814645, 32183301, 33436325, 35047863, 33646313, 25882375, 19781682, 36361687, 26580448, 34921020, 35264596, 33415580, 28652578, 20305132) - |
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute | - | - - |
Hereditary cancer-predisposing syndrome Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 04, 2024 | This missense variant replaces arginine with histidine at codon 337 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 20305132, 23555315, 25186627, 29522266, 30303537, 33471991) or prostate cancer (PMID: 33436325), but also in control individuals (PMID: 23555315, 30303537, 33471991). This variant has been identified in 20/251160 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 | curation | Sema4, Sema4 | Jan 14, 2022 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 26, 2019 | 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. - |
Familial cancer of breast Uncertain:2Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Apr 24, 2024 | 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]. - |
Uncertain significance, criteria provided, single submitter | clinical testing | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Nov 17, 2022 | The ATM c.1010G>A (p.Arg337His) missense change has a maximum subpopulation frequency of 0.012% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. This variant has been reported in individuals with breast and/or cancer (PMID: 30303537, 33646313) and in individuals with prostate cancer (PMID: 33436325) and pancreatic cancer (PMID: 35047863). This variant is present in three individuals in a database of women older than 70 years of age who have never had cancer (FLOSSIES database, https://whi.color.com/). To our knowledge, this variant has not been reported in individuals with ataxia telangiectasia. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Division of Medical Genetics, University of Washington | Oct 08, 2019 | This variant has been reported in the literature in individuals with breast cancer (Tung 2015, Decker 2017, Hauke 2018). This variant has an overall allele frequency of 0.00008 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). In silico analyses indicate this is an evolutionarily conserved residue. PP3 - |
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 08, 2023 | Variant summary: ATM c.1010G>A (p.Arg337His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.5e-05 in 271398 control chromosomes (gnomAD and publications). This frequency is not higher than the estimated maximum expected for a pathogenic variant in ATM causing Breast Cancer (0.001), allowing no conclusion about variant significance. c.1010G>A has been reported in the literature in individuals affected with Breast Cancer and other tumor phenotypes, including prostate cancer and pediatric retinoblastoma (e.g. Bernstein_2010, Zhang_2015, Tung_2015, Decker_2017, Hauke_2018, Girard_2019, Karlsson_2021, Dorling_2021), but was also found in healthy controls (e.g. Tiao_2017, Girard_2019, Dorling_2021, and in three women older than 70 years of age who have never had cancer, in the FLOSSIES database). These reports 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. The following publications have been ascertained in the context of this evaluation (PMID: 25882375, 24356096, 20305132, 28779002, 22529920, 30303537, 29522266, 30814645, 28652578, 25186627, 26580448, 33436325, 33471991). Ten other submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, mostly without evidence for independent evaluation, and classified the variant as VUS (n=7), likely benign (n=2) or benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Ataxia-telangiectasia syndrome Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Mendelics | Apr 09, 2024 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
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 | Dec 30, 2022 | - - |
Malignant tumor of breast Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The ATM p.Arg337His variant was not identified in the literature nor was it identified in the COGR, MutDB, LOVD 3.0, and ATM-LOVD databases or the NHLBI GO Exome Sequencing Project. The variant was identified in dbSNP (ID: rs202160435) as “With Uncertain significance allele”, in ClinVar and Clivitae databases with uncertain significance by GeneDx, Ambry Genetics and Invitae); in the Cosmic database 12X in bladder, colon, rectal, gallbladder and stomach carcinomas. The variant was also identified in the 1000 Genomes Project in 2 of 5000 chromosomes (frequency: 0.0004). The variant was identified in control databases in 19 of 245972 chromosomes at a frequency of 0.000077 in the following populations: African in 1 of 15292chromosomes (freq. 0.00007), Latino in 2 of 33536 chromosomes (freq. 0.00006), European Non-Finnish in 15 of 111508 chromosomes (freq. 0.0001), South Asian in 1 of 30782 chromosomes (freq. 0.00003), but was not seen in Ashkenazi Jewish, East Asian, European Finnish and Other populations, increasing the likelihood that this may be a low frequency variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017). The p.Arg337His residue is conserved in mammals but not in more distantly related organisms and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in-silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The variant is located with the Armadillo-type fold functional domain. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at