rs376824528
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_000051.4(ATM):c.7816A>G(p.Ile2606Val) variant causes a missense change. The variant allele was found at a frequency of 0.000018 in 1,613,192 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict 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. I2606M) has been classified 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 -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.7816A>G | p.Ile2606Val | missense_variant | 53/63 | ENST00000675843.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATM | ENST00000675843.1 | c.7816A>G | p.Ile2606Val | missense_variant | 53/63 | NM_000051.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000394 AC: 6AN: 152174Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000160 AC: 4AN: 250604Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135450
GnomAD4 exome AF: 0.0000157 AC: 23AN: 1461018Hom.: 0 Cov.: 31 AF XY: 0.0000165 AC XY: 12AN XY: 726842
GnomAD4 genome ? AF: 0.0000394 AC: 6AN: 152174Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74334
ClinVar
Submissions by phenotype
Ataxia-telangiectasia syndrome Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 2606 of the ATM protein (p.Ile2606Val). This variant is present in population databases (rs376824528, gnomAD 0.004%). This missense change has been observed in individual(s) with prostate cancer (PMID: 33436325). ClinVar contains an entry for this variant (Variation ID: 187077). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Studies have shown that this missense change is associated with inconclusive levels of altered splicing (Invitae). 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | Jul 02, 2018 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 08, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 24, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies suggest a minimal effect on splicing compared to controls (Dragos et al., 2022); Observed in individuals with a personal and/or family history of breast, ovarian, prostate, and other cancers (Tung et al., 2015; Karlsson et al., 2021; Andrikopoulou et al., 2022; Dragos et al., 2022); This variant is associated with the following publications: (PMID: 23338612, 25428177, 33436325, 35806449, 36531003, 25186627) - |
Familial cancer of breast Uncertain:2Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Mar 31, 2023 | 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 | Baylor Genetics | Mar 30, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Department of Molecular Diagnostics, Institute of Oncology Ljubljana | May 15, 2022 | ATM:c.7816A>G variant is predicted to create a de novo donor ss 28 bp upstream of natural splice site. Functional RNA study has shown that the variant may cause minimally expressed whole exon 53 skipping (PMID: 35806449). Missense in silico tools predict that the variant does not have an impact on protein function (REVEL 0.26). Therefore the variant was classified as variant of uncertain significance (ACMG/AMP: PP3) - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 31, 2023 | The p.I2606V variant (also known as c.7816A>G), located in coding exon 52 of the ATM gene, results from an A to G substitution at nucleotide position 7816. The isoleucine at codon 2606 is replaced by valine, an amino acid with highly similar properties. This alteration has been identified in individuals with a personal and/or family history of breast cancer (Tung N et al. Cancer, 2015 Jan;121:25-33; Pereira JZ et al. Mol Biol Rep, 2022 Oct;49:9509-9520). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. RNA studies have demonstrated that this alteration results in an incomplete splice defect; the clinical impact of this abnormal splicing is unknown at this time (Ambry internal data). 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 | Dec 21, 2022 | This missense variant replaces isoleucine with valine at codon 2606 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). RNA studies have showed this variant causes a minor increase in exon 53 skipping (PMID: 35806449). This variant has been reported in individuals affected with breast cancer (PMID: 25186627, 35806449), ovarian cancer (PMID: 36531003), or prostate cancer (PMID: 33436325). In a large international case-control study, this variant was reported in 5/60461 breast cancer cases and 5/53456 controls (OR=0.884, 95%CI 0.256 to 3.054, p-value=1; PMID: 33471991). This variant has also been identified in 4/250604 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
Uncertain significance, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | May 03, 2020 | - - |
Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jul 02, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at