11-108289740-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP3
The NM_000051.4(ATM):c.4375G>A(p.Gly1459Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000169 in 1,613,574 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).
Frequency
Consequence
NM_000051.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
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ATM | NM_000051.4 | c.4375G>A | p.Gly1459Arg | missense_variant | Exon 29 of 63 | ENST00000675843.1 | NP_000042.3 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000118 AC: 18AN: 152166Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000478 AC: 12AN: 251208Hom.: 0 AF XY: 0.0000663 AC XY: 9AN XY: 135774
GnomAD4 exome AF: 0.000174 AC: 254AN: 1461408Hom.: 0 Cov.: 31 AF XY: 0.000175 AC XY: 127AN XY: 726992
GnomAD4 genome AF: 0.000118 AC: 18AN: 152166Hom.: 0 Cov.: 32 AF XY: 0.0000942 AC XY: 7AN XY: 74334
ClinVar
Submissions by phenotype
not provided Uncertain:4
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; Observed in individuals with leukemia, breast cancer, and Lynch-syndrome associated cancers and/or polyps but also in healthy controls (PMID: 17623063, 19781682, 25980754, 26580448, 26976419, 28652578, 28779002, 29458332, 30374176, 33471991); This variant is associated with the following publications: (PMID: 19781682, 26976419, 28779002, 25980754, 17623063, 29458332, 30374176, 26580448, 28652578, 33436325, 35098669, 33471991) -
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). Computational tools predict that this variant is damaging. -
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Hereditary cancer-predisposing syndrome Uncertain:4
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The p.G1459R variant (also known as c.4375G>A), located in coding exon 28 of the ATM gene, results from a G to A substitution at nucleotide position 4375. The glycine at codon 1459 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been detected in individuals diagnosed with breast cancer and healthy controls across numerous studies (Tavtigian S et al. Am. J. Hum. Genet. 2009 Oct;85:427-46; Decker B et al. J. Med. Genet. 2017 Nov;54:732-741; Tung N et al. J. Clin. Oncol. 2016 May;34:1460-8; Edvardsen H et al. Radiat Oncol. 2007 Jul;2:25). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -
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This missense variant replaces glycine with arginine at codon 1459 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. The variant has been reported in individuals affected with breast cancer (PMID: 17623063, 26976419, 28779002, 33471991), prostate cancer (PMID: 33436325), colorectal cancer (PMID: 29458332), an individual suspected of Lynch syndrome (PMID: 25980754), and in healthy controls (PMID: 19781682, 28779002, 33471991). This variant has also been identified in 16/282612 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. -
Ataxia-telangiectasia syndrome Uncertain:3
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1459 of the ATM protein (p.Gly1459Arg). This variant is present in population databases (rs145667735, gnomAD 0.01%). This missense change has been observed in individual(s) with breast cancer and/or prostate cancer (PMID: 17623063, 25980754, 26976419, 29458332, 30374176, 33436325). ClinVar contains an entry for this variant (Variation ID: 127387). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt ATM protein function with a negative predictive value of 95%. 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. -
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The ATM c.4375G>A (p.Gly1459Arg) missense change has a maximum subpopulation frequency of 0.01% 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 functional studies have not been performed. 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. -
not specified Uncertain:2
Variant summary: ATM c.4375G>A (p.Gly1459Arg) 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 5.1e-05 in 256006 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing Breast Cancer (5.1e-05 vs 0.001), allowing no conclusion about variant significance. c.4375G>A has been reported in the literature as a VUS in settings of multigene panel testing in individuals affected with breast/colorectal/pediatric and other cancers (example, Edvardsen_2007, Tung_2016, Yurgelun_2015, Dominguez-Valentin_2018, Zhang_2015, Tsai_2019) but also in controls (example, Tavtigian_2009, Dorling_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Breast Cancer/Ataxia Telangiectasia. At-least one co-occurrence with another pathogenic variant has been reported (BRCA2 variant not specified, Tsai_2019). 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: 29458332, 17623063, 19781682, 30374176, 26976419, 25980754, 26580448). ClinVar contains an entry for this variant (Variation ID: 127387). Based on the evidence outlined above, the variant was classified as uncertain significance. -
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Familial cancer of breast Uncertain:1Benign:1
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]. -
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Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast Uncertain:1
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ATM-related disorder Uncertain:1
The ATM c.4375G>A variant is predicted to result in the amino acid substitution p.Gly1459Arg. This variant has been documented in individuals with suspected Lynch syndrome (Table S2, Yurgelun et al. 2015. PubMed ID: 25980754; Dominguez-Valentin et al. 2018. PubMed ID: 29458332), breast cancer (Table A2, Tung et al. 2016. PubMed ID: 26976419; Additional File 1, Edvardsen et al. 2007. PubMed ID: 17623063), and prostate cancer (Table S4, Karlsson et al. 2021. PubMed ID: 33436325). However, Tavtigian et al. has observed this variant only in the control group in a large case-control-based study on breast cancer (Table S2, Tavtigian et al. 2009. PubMed ID: 19781682). This variant is reported in 0.012% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-108160467-G-A). In ClinVar, it is classified as a variant of uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/127387/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Hereditary breast ovarian cancer syndrome Uncertain:1
This sequence variant is a single nucleotide substitution (G>A) that results in a glycine to arginine amino acid change at residue 1459 in the ATM protein. This is a previously reported variant (ClinVar) that has been observed in at least one breast cancer patient (PMID 26976419), two patients being tested for Lynch syndrome (PMID 25980754), a patient with familial colorectal cancer (PMID 29458332), and one healthy control with no cancer (PMID 19781682). This variant is rare in control population datasets (gnomAD database, 16/276984 alleles, .006% overall frequency). A meta-analysis in breast cancer patients did not identify any enrichment of this variant in breast cancer cases versus healthy controls (PMID 19781682). The Gly1459 residue is not located in a known functional domain, and studies assessing the effect of this variant on ATM function are not published in the literature, to our knowledge. However, multiple in silico tools queried predict that this glycine to arginine amino acid change would be damaging. The glycine at this position is highly evolutionarily conserved across mammalian species examined. At this time, there is insufficient evidence to determine if this variant is pathogenic or benign. Therefore, we consider the significance of this variant to be uncertain. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at