11-108246993-A-G
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_000051.4(ATM):āc.931A>Gā(p.Ile311Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000372 in 1,612,418 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 ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I311T) 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.931A>G | p.Ile311Val | missense_variant | 8/63 | ENST00000675843.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATM | ENST00000675843.1 | c.931A>G | p.Ile311Val | missense_variant | 8/63 | NM_000051.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152214Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000797 AC: 2AN: 250896Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135700
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1460204Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3AN XY: 726466
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152214Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74366
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:3
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Sep 14, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 07, 2023 | The p.I311V variant (also known as c.931A>G), located in coding exon 7 of the ATM gene, results from an A to G substitution at nucleotide position 931. The isoleucine at codon 311 is replaced by valine, an amino acid with highly similar properties. This variant was detected in a Spanish family with hereditary breast and ovarian cancer (HBOC) (Tavera-Tapia A et al. Breast Cancer Res Treat, 2017 02;161:597-604). This amino acid position is not well 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jun 15, 2021 | This missense variant replaces isoleucine with valine at codon 311 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 2/250896 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:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 22, 2022 | This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 311 of the ATM protein (p.Ile311Val). This variant is present in population databases (no rsID available, gnomAD 0.006%). This missense change has been observed in individual(s) with ATM-related cancer (PMID: 27913932). ClinVar contains an entry for this variant (Variation ID: 229990). 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. - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Feb 15, 2021 | - - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 20, 2017 | Variant summary: The ATM c.931A>G (p.Ile311Val) variant located in the Armadillo-type fold domain (via InterPro) involves the alteration of a conserved nucleotide and 4/4 in silico tools (SNPsandGO not captured due to low reliability index) predict a benign outcome, although these predictions have yet to be functionally assessed. The variant of interest was not observed in the large, broad control population, ExAC, 0/120068 control chromosomes. A publication cites the variant in an HBOC individual with limited information (ie, lack of co-occurrence and cosegregation data). In addition, multiple clinical diagnostic laboratories classified this variant as uncertain significance. Therefore, until additional information becomes available (ie, clinical and functional studies), the variant of interest has been classified as a "Variant of Uncertain Significance (VUS)." - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 03, 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; Observed in individuals with breast and/or ovarian cancer (Tavera-Tapia et al., 2017); This variant is associated with the following publications: (PMID: 33471991, 27913932) - |
Familial cancer of breast Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 25, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at