chr11-108301655-G-C
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM1BP4BP6
The NM_000051.4(ATM):āc.5185G>Cā(p.Val1729Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000899 in 1,613,474 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1729A) has been classified as Uncertain significance.
Frequency
Consequence
NM_000051.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.5185G>C | p.Val1729Leu | missense_variant | 35/63 | ENST00000675843.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATM | ENST00000675843.1 | c.5185G>C | p.Val1729Leu | missense_variant | 35/63 | NM_000051.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000112 AC: 17AN: 152116Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000995 AC: 25AN: 251144Hom.: 0 AF XY: 0.0000958 AC XY: 13AN XY: 135726
GnomAD4 exome AF: 0.0000876 AC: 128AN: 1461358Hom.: 0 Cov.: 31 AF XY: 0.0000949 AC XY: 69AN XY: 726986
GnomAD4 genome AF: 0.000112 AC: 17AN: 152116Hom.: 0 Cov.: 32 AF XY: 0.000135 AC XY: 10AN XY: 74308
ClinVar
Submissions by phenotype
not provided Uncertain:8
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 19, 2023 | Observed in individuals with ataxia-telangiectasia, including one individual who also carried a homozygous pathogenic ATM variant and another who carried a heterozygous ATM pathogenic variant on the opposite allele (in trans) (PMID: 17124347, 29482223, 33779842); Observed in individuals with breast, colorectal, uterine, and prostate cancer (PMID: 28640387, 29522266, 29684080, 30303537, 33436325, 35264596); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 11443540, 17124347, 22529920, 28640387, 29482223, 28652578, 29684080, 29522266, 19781682, 26689913, 30303537, 33203166, 33436325, 32522261, 35980532, 35264596, 37450374, 34482403, 33779842) - |
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The ATM p.Val1729Leu variant was identified in 3 of 9436 proband chromosomes (frequency: 0.0003) from individuals or families with cerebellar ataxia, Ataxia telangiectasia, and colorectal cancer, and was present in 2 of 4676 control chromosomes (frequency: 0.0004) from healthy individuals (Coutelier 2018, Magliozzi 2006, Ricker 2017, Tavtigian 2009, Thorstenson 2001). The variant was also identified in the following databases: dbSNP (ID: rs3092907) as "With Uncertain significance allele", ClinVar (1x likely benign, 3x uncertain significance), and Clinvitae. The variant was not identified in COGR, Cosmic, MutDB, LOVD 3.0, or ATM-LOVD. The variant was identified in control databases in 28 of 276848 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: Other in 6 of 6458 chromosomes (freq: 0.0009), Latino in 6 of 34416 chromosomes (freq: 0.0002), and European in 16 of 126392 chromosomes (freq: 0.0001); it was not observed in the African, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. Multiple studies list this variant as a polymorphism and one study found this variant co-occurring with the ATM homozygous pathogenic variant c.9022C>T (p.R3008C) (Magliozzi 2006, Thorstenson 2001, Coutelier 2018), increasing the likelihood this variant may not have clinical significance. The p.Val1729 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. - |
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute | - | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jan 20, 2020 | The frequency of this variant in the general population, 0.00017 (6/35438 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with ataxia telangiectasia (AT) (PMID: 33779842 (2021), 17124347 (2006)) or cerebellar ataxia (PMID: 29482223 (2018)). It has also been reported in individuals with breast cancer (PMID: 33471991 (2021), 30303537 (2019), 29522266 (2018)), uterine cancer (PMID: 29684080 (2018)), prostate cancer (PMID: 33436325 (2021)), or colorectal cancer (PMID: 28640387 (2017)). This variant is also reported in individuals unaffected by cancer (PMID: 33471991 (2021), 28652578 (2017), FLOSSIES (http://whi.color.com/)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. - |
Uncertain significance, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jan 20, 2020 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Hereditary cancer-predisposing syndrome Uncertain:2Benign:3
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 28, 2018 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 04, 2016 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | Mar 10, 2022 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | True Health Diagnostics | Feb 23, 2018 | - - |
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Jan 08, 2021 | - - |
not specified Uncertain:3
Uncertain significance, no assertion criteria provided | clinical testing | Genetic Services Laboratory, University of Chicago | Jul 14, 2022 | DNA sequence analysis of the ATM gene demonstrated a sequence change, c.5185G>C, in exon 35 that results in an amino acid change, p.Val1729Leu. This sequence change has been described in the gnomAD database with a frequency of 0.017% in the Latino subpopulation (dbSNP rs3092907). The p.Val1729Leu change affects a moderately conserved amino acid residue located in a domain of the ATM protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Val1729Leu substitution. This sequence change has been reported in one individual with breast cancer (PMID: 30303537). It has also been detected in the homozygous state in one individual with a metabolic presentation ataxia (PMID: 29482223) and in trans with a pathogenic variant in a family with ataxia telangiectasia (PMID: 33779842). Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Val1729Leu change remains unknown at this time. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 27, 2023 | Variant summary: ATM c.5185G>C (p.Val1729Leu) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 251330 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing Ataxia-Telangiectasia (0.0001 vs 0.004), allowing no conclusion about variant significance. c.5185G>C has been reported in the literature as a "polymorphism" in a study of individuals affected with Ataxia-Telangiectasia, as a VUS in settings of multigene panel testing in an individual with a personal and/or family history of breast cancer and in unaffected controls (example, Magliozzi_2006, Tavtigian_2009, Pereira_2022). In one family the variant is reported to segregate with disease (example: Shalash_2021). However, these reports do not provide unequivocal conclusions about a penetrant association of the variant with Ataxia-Telangiectasia/ATM-related cancers. The following publications have been ascertained in the context of this evaluation (PMID: 22529920, 35264596, 33436325, 17124347, 35980532, 33779842, 19781682, 11443540). Multiple submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments (likely benign, n=4; VUS, n=8). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Feb 06, 2024 | - - |
Familial cancer of breast Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jan 01, 2019 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | May 22, 2024 | 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]. - |
Ataxia-telangiectasia syndrome Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Mendelics | Apr 09, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at