rs550552791
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM1PP3BP6
The NM_000051.4(ATM):c.4724G>A(p.Arg1575His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000893 in 1,612,438 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1575C) 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 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.4724G>A | p.Arg1575His | missense_variant | 31/63 | ENST00000675843.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATM | ENST00000675843.1 | c.4724G>A | p.Arg1575His | missense_variant | 31/63 | NM_000051.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000461 AC: 7AN: 152008Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000598 AC: 15AN: 250980Hom.: 0 AF XY: 0.0000516 AC XY: 7AN XY: 135664
GnomAD4 exome AF: 0.0000938 AC: 137AN: 1460430Hom.: 0 Cov.: 30 AF XY: 0.0000853 AC XY: 62AN XY: 726640
GnomAD4 genome ? AF: 0.0000461 AC: 7AN: 152008Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2AN XY: 74238
ClinVar
Submissions by phenotype
not provided Uncertain:5
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jan 16, 2023 | Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity (http://gnomad.broadinstitute.org). Assessment of experimental evidence regarding the effect of this variant on protein function suggests it has no effect relevant to disease. (PMID: 19431188) - |
Uncertain significance, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Feb 17, 2017 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 21, 2022 | Observed in individuals with ATM-related and other cancers, but also in unaffected controls (Austen et al., 2008; Tavtigian et al., 2009; Skowronska et al., 2012; Navrkalova et al., 2013; Zhang et al., 2015; Pearlman et al., 2017; Hauke et al., 2018; Momozawa et al., 2018); Published functional studies demonstrate no damaging effect: kinase activity similar to wild type (Austen et al., 2008; Barone et al., 2009); 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: 18573109, 26580448, 19781682, 23585524, 26787654, 21933854, 26689913, 27720647, 29522266, 19431188, 30287823, 27978560, 33922147, 30613976) - |
Ataxia-telangiectasia syndrome Uncertain:2Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 19, 2024 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 03, 2023 | This missense variant replaces arginine with histidine at codon 1575 of the ATM protein. Computational prediction suggests that this variant may not affect protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have shown that this variant does not affect kinase activity of ATM protein (PMID: 18573109, 19431188). This variant has been reported in individuals affected with breast cancer, chronic lymphocytic leukemia, and rectal cancer (PMID: 19781682, 23585524, 27978560, 30287823, 36200007), and in unaffected individuals (PMID: 21933854, 30287823, 34262154). This variant has been detected in a breast cancer case-control meta-analysis in 8/60458 breast cancer cases and 6/53455 controls (OR=1.179, 95%CI 0.409 to 3.398, p-value=0.796; PMID: 33471991). This variant has been identified in 16/282324 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 | Mar 30, 2023 | The p.R1575H variant (also known as c.4724G>A), located in coding exon 30 of the ATM gene, results from a G to A substitution at nucleotide position 4724. The arginine at codon 1575 is replaced by histidine, an amino acid with highly similar properties. This alteration has been detected in individuals diagnosed with breast cancer and control individuals across numerous studies (Tavtigian S et al. Am. J. Hum. Genet. 2009 Oct;85(4):427-46; Hauke J et al. Cancer Med, 2018 04;7:1349-1358; Momozawa Y et al. Nat Commun, 2018 10;9:4083; Rizzolo P et al. Int J Cancer, 2019 07;145:390-400; Mittal A et al. Ecancermedicalscience, 2022 Aug;16:1434). This alteration has also been identified in individuals diagnosed with CLL, medulloblastoma and early onset colorectal cancer (Skowronska A et al. Haematologica 2012 Jan;97:142-6; Zhang J et al. N Engl J Med, 2015 Dec;373:2336-2346; Pearlman R et al. JAMA Oncol. 2017 Apr;3(4):464-471). Functional analysis of this alteration found normal protein levels and kinase activity compared to wild type (Austen B et al. Br. J. Haematol. 2008 Sep;142(6):925-33; Barone G et al. Hum. Mutat. 2009 Aug;30:1222-30). This amino acid position is highly 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. - |
Familial cancer of breast Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | May 20, 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 | Division of Medical Genetics, University of Washington | Jun 27, 2019 | The c.4724G>A variant has been reported in the literature to co-occur with the ATM c.6820G>A variant in individuals with breast cancer, chronic lymphocytic leukemia (CLL) and multiple myeloma (Austen 2008, Tavtigian 2008, and Navrkalova 2012). The individual with CLL also had a somatic ATM Gln984Glu and a somatic 11q chromosomal deletion. The c.4724G>A variant has a combined allele frequency of 0.00006 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). In silico analyses indicate that this variant is in an evolutionarily conserved residue. Thus, it is unknown whether this variant increases cancer risk. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 16, 2023 | Variant summary: ATM c.4724G>A (p.Arg1575His) 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 5.9e-05 in 255778 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing Breast Cancer (5.9e-05 vs 0.001), allowing no conclusion about variant significance. c.4724G>A has been reported in the literature in individuals affected with Breast Cancer (e.g. Tavtigian_2009, Momozawa_2018, Rizzolo_2019, Bhai_2021), and in individuals with a variety of other cancers (e.g. Austen_2008, Navrkalova_2012, Pearlman_2016, Lu_2015), but also in healthy controls (e.g. Momozawa_2018, Dalmasso_2021). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. At least one publication reports experimental evidence evaluating an impact on protein function and found no damaging effect of this variant on ATM kinase activity (Austen_2008). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Seven submitters classified the variant as uncertain significance and one classified it as likely benign. The following publications have been ascertained in the context of this evaluation (PMID: 18573109, 34262154, 26689913, 30287823, 23585524, 27978560, 19781682, 26787654, 30613976, 34326862). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at