chr11-108271074-T-G
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PP3_StrongPP5_Very_Strong
The NM_000051.4(ATM):āc.2849T>Gā(p.Leu950Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000144 in 1,461,664 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 Likely pathogenic (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L950F) has been classified as Uncertain significance.
Frequency
Consequence
NM_000051.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.2849T>G | p.Leu950Arg | missense_variant | 19/63 | ENST00000675843.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATM | ENST00000675843.1 | c.2849T>G | p.Leu950Arg | missense_variant | 19/63 | NM_000051.4 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 0.0000144 AC: 21AN: 1461664Hom.: 0 Cov.: 32 AF XY: 0.0000151 AC XY: 11AN XY: 727156
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Ataxia-telangiectasia syndrome Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 19, 2024 | This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 950 of the ATM protein (p.Leu950Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with pancreatic cancer and ataxia-telangiectasia (PMID: 10873394, 12552559, 20678261, 21792198, 27989354). ClinVar contains an entry for this variant (Variation ID: 186574). 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 disruptive. Experimental studies have shown that this missense change affects ATM function (PMID: 10873394, 20678261). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | May 06, 2019 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 06, 2023 | The p.L950R variant (also known as c.2849T>G), located in coding exon 18 of the ATM gene, results from a T to G substitution at nucleotide position 2849. The leucine at codon 950 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been reported in multiple individuals diagnosed with ataxia telangiectasia (Becker-Catania SG et al. Mol. Genet. Metab. 2000 Jun;70:122-33; Buzin CH et al. Hum. Mutat. 2003 Feb;21:123-31; Reiman A et al. Br. J. Cancer 2011 Aug;105(4):586-91). This alteration was reported in a patient diagnosed with breast cancer as well as patient with localized prostate cancer (Yadav S et al. J Clin Oncol. 2020 05;38:1409-1418; Na R et al. Eur. Urol. 2017 May;71:740-747). Two studies have demonstrated that this alteration leads to lack of ATM protein expression (Becker-Catania SG et al. Mol. Genet. Metab. 2000 Jun;70:122-33; Fang Z et al. Genome Integr. 2010 Jun;1:9). 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 majority of available evidence to date, this variant is likely to be pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 07, 2021 | This missense variant replaces leucine with arginine at codon 950 in the beta-adaptin interaction domain of the ATM protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with ataxia telangiectasia (PMID: 10873394, 12552559, 20678261, 21792198), breast cancer (Color internal data), and prostate cancer (PMID: 27989354). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. - |
Familial cancer of breast Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Jan 23, 2024 | This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 10873394, 21792198, 20678261]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 10873394, 21792198, 12552559, 20678261]. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 06, 2024 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 27, 2023 | 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; This variant is associated with the following publications: (PMID: 21792198, 10330348, 30128536, 10873394, 20678261, 15928302, 27989354, 27304073, 28873162, 19781682, 34771661, 27535533, 32125938, 12552559, 36346689) - |
Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast Other:1
not provided, no classification provided | phenotyping only | GenomeConnect - Invitae Patient Insights Network | - | Variant interpreted as Likely pathogenic and reported on 03-14-2020 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at