11-108325478-T-G
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_000051.4(ATM):āc.6741T>Gā(p.Ile2247Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,613,590 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
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 | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.6741T>G | p.Ile2247Met | missense_variant | 46/63 | ENST00000675843.1 | NP_000042.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ATM | ENST00000675843.1 | c.6741T>G | p.Ile2247Met | missense_variant | 46/63 | NM_000051.4 | ENSP00000501606.1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152122Hom.: 0 Cov.: 30
GnomAD3 exomes AF: 0.00000797 AC: 2AN: 250806Hom.: 0 AF XY: 0.00000738 AC XY: 1AN XY: 135556
GnomAD4 exome AF: 0.00000547 AC: 8AN: 1461468Hom.: 0 Cov.: 33 AF XY: 0.00000688 AC XY: 5AN XY: 727050
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152122Hom.: 0 Cov.: 30 AF XY: 0.0000135 AC XY: 1AN XY: 74322
ClinVar
Submissions by phenotype
Ataxia-telangiectasia syndrome Uncertain:2
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Feb 11, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 19, 2022 | This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 2247 of the ATM protein (p.Ile2247Met). This variant is present in population databases (no rsID available, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with ATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 230515). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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. - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Aug 15, 2022 | This missense variant replaces isoleucine with methionine at codon 2247 of the ATM protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 25186627). This variant has also been identified in 2/250806 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 | Aug 29, 2023 | The p.I2247M variant (also known as c.6741T>G), located in coding exon 45 of the ATM gene, results from a T to G substitution at nucleotide position 6741. The isoleucine at codon 2247 is replaced by methionine, an amino acid with highly similar properties. This alteration was previously detected on a 25-gene panel test in a woman of Western/Northern European ancestry who was diagnosed with breast cancer before age 50 (Tung N et al. Cancer, 2015 Jan;121:25-33). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 06, 2023 | Variant summary: ATM c.6741T>G (p.Ile2247Met) results in a conservative amino acid change located in the PIK-related kinase domain (IPR014009) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 250806 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.6741T>G has been reported in the literature in an individual affected with Breast Cancer, co-occurring with a CHEK2 pathogenic variant (c.1100delC, p.Thr367MetfsX15) (Tung_2014). These report(s) 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. Six ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 04, 2021 | Not observed at significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer (Tung 2015); This variant is associated with the following publications: (PMID: 23532176, 25186627) - |
Familial cancer of breast Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 26, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at