rs587782255
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4
The NM_000051.4(ATM):c.2414G>A(p.Arg805Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000109 in 1,461,514 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 (★★).
Frequency
Consequence
NM_000051.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.2414G>A | p.Arg805Gln | missense_variant | Exon 16 of 63 | ENST00000675843.1 | NP_000042.3 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.0000279 AC: 7AN: 251236Hom.: 0 AF XY: 0.0000442 AC XY: 6AN XY: 135828
GnomAD4 exome AF: 0.0000109 AC: 16AN: 1461514Hom.: 0 Cov.: 31 AF XY: 0.0000165 AC XY: 12AN XY: 727066
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Uncertain:4
In silico analysis indicates that this missense variant does not alter protein structure/function; Observed in individuals with breast or prostate cancer, but also seen in unaffected controls (PMID: 17393301, 19781682, 25186627, 33436325, 33471991); This variant is associated with the following publications: (PMID: 25186627, 17393301, 20224443, 19781682, 27311873, 30197789, 33436325, 33471991) -
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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 not damaging. -
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Familial cancer of breast Uncertain:3
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The missense variant in c.2414G>A (p.Arg805Gln) in ATM gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Arg805Gln variant is reported with the allele frequency of 0.002786% in gnomAD and is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as uncertain significance. The amino acid Arg at position 805 is changed to a Gln changing protein sequence and it might alter its composition and physico-chemical properties. In silico tools predict the variant to be tolerated. The residue is conserved across species. The amino acid change p.Arg805Gln in ATM is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance. -
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 805 of the ATM protein (p.Arg805Gln). This amino acid position is highly conserved. This variant is present in population databases (rs587782255, gnomAD 0.02%). This missense change has been observed in individual(s) with breast cancer and prostate cancer (PMID: 17393301, 19781682, 33436325). ClinVar contains an entry for this variant (Variation ID: 142128). n addition, the in silico prediction for this alteration is inconclusive.. 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. Heterozygous pathogenic/likely pathogenic mutations in the ATM gene are associated with susceptibility to breast cancer (OMIM 114480 ). -
Ataxia-telangiectasia syndrome Uncertain:2
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 805 of the ATM protein (p.Arg805Gln). This variant is present in population databases (rs587782255, gnomAD 0.02%). This missense change has been observed in individual(s) with breast cancer and prostate cancer (PMID: 17393301, 19781682, 33436325). ClinVar contains an entry for this variant (Variation ID: 142128). 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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Hereditary cancer-predisposing syndrome Uncertain:2
The p.R805Q variant (also known as c.2414G>A), located in coding exon 15 of the ATM gene, results from a G to A substitution at nucleotide position 2414. The arginine at codon 805 is replaced by glutamine, an amino acid with highly similar properties. This variant has been previously detected in breast cancer patients (Tavtigian SV et al. Am. J. Hum. Genet. 2009 Oct;85:427-46; Tung N et al. Cancer, 2015 Jan;121:25-33). This variant has also been reported in 1/5560 prostate cancer cases and in 0/3353 controls of European ancestry (Karlsson Q et al. Eur Urol Oncol, 2021 08;4:570-579). This alteration has been reported in the germline of 1 of 8,920 ethnically matched normal population control subjects but was not seen in 516 samples from a study of chronic lymphocytic leukemia patients of European descent (Tiao G et al. Leukemia, 2017 10;31:2244-2247). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -
This missense variant replaces arginine with glutamine at codon 805 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. In a large international case-control study, this variant was reported in 0/60466 breast cancer cases and 4/53457 controls (PMID: 33471991). This variant has been reported in several individuals affected with breast cancer (PMID: 17393301, 19781682). This variant has been observed in an individual affected with breast and ovarian cancer, who carried a pathogenic BRCA1 variant (Color internal data). This variant has been identified in 7/251236 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. -
not specified Uncertain:1
Variant summary: ATM c.2414G>A (p.Arg805Gln) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251236 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2414G>A has been reported in the literature in individuals affected with breast cancer and prostate cancer (e.g. Broeks_2008, Tavtigian_2009, Tung_2015, Karlsson_2021). These reports do not provide unequivocal conclusions about association of the variant with breast or prostate 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: 17393301, 33436325, 19781682, 25186627). ClinVar contains an entry for this variant (Variation ID: 142128). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at