ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.875C>T (p.Pro292Leu)

gnomAD frequency: 0.00001  dbSNP: rs747727055
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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen RCV003468983 SCV004565389 likely pathogenic Familial cancer of breast 2024-01-25 reviewed by expert panel curation The c.875C>T variant in ATM is a missense variant predicted to cause substitution of proline by leucine at amino acid 292 (p.Pro292Leu). This variant has been detected in at least 3 individuals with Ataxia-Telangiectasia (PMID: 18634022, 30549301, 26896183). The highest population minor allele frequency in gnomAD v2.1.1 is 0.005% (1/19890 alleles) in the East Asian population (PM2_Supporting, BS1, and BA1 are not met). Experimental studies shows that this variant has impact on ATM kinase activity, protein levels and radiosensitivity was also found to be sensitive (RS<21%) when compared with wild type (PMID:18634022,19431188). The REVEL computational prediction analysis tool predicted a score of 0.752, which is above the threshold necessary to apply PP3. In summary, this variant meets criteria to be classified as likely pathogenic for autosomal dominant hereditary breast cancer and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (PM3_strong, PS3_Moderate, PP3)
Ambry Genetics RCV000220769 SCV000273133 pathogenic Hereditary cancer-predisposing syndrome 2024-05-10 criteria provided, single submitter clinical testing The p.P292L pathogenic mutation (also known as c.875C>T), located in coding exon 6 of the ATM gene, results from a C to T substitution at nucleotide position 875. The proline at codon 292 is replaced by leucine, an amino acid with similar properties. This alteration has been detected both as the only mutation and in conjunction with a second mutation in individuals with a clinical diagnosis of ataxia-telangiectasia (A-T), two of whom have had a typical phenotype and two of whom had a mild phenotype (Stankovic T et al. Am. J. Hum. Genet. 1998 Feb;62:334-45; Becker-Catania SG et al. Mol. Genet. Metab. 2000 Jun;70:122-33; Mitui M et al. Hum. Mutat., 2009 Jan;30:12-21; Schon K et al. Ann. Neurol., 2019 02;85:170-180). This alteration was also identified in individuals diagnosed with breast and/or ovarian cancer (Kansuttiviwat C et al. NPJ Genom Med, 2024 Feb;9:9). Functional analyses of p.P292L have shown reduced kinase activity, reduced protein levels, and increased radiosensitivity compared to wildtype ATM (Mitui M et al. Hum. Mutat., 2009 Jan;30:12-21; Barone G et al. Hum. Mutat., 2009 Aug;30:1222-30). 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 supporting evidence, this variant is interpreted as a disease-causing mutation.
GeneDx RCV000255507 SCV000322064 pathogenic not provided 2024-06-17 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect: reduced ATM protein levels, reduced or absent kinase activity, and higher levels of radiosensitivity after exposure to ionizing radiation (PMID: 9463314, 10873394, 19431188, 18634022, 21792198); Observed in individuals with ATM-related cancers in published literature (PMID: 32694154, 31948886, 32957588); 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: 25040471, 25482724, 36113475, 22529920, 12673797, 15279807, 12072877, 12552559, 15928302, 19431188, 21792198, 28359806, 9463314, 29922827, 30549301, 31948886, 10873394, 34404389, 32957588, 32694154, 26896183, 18634022, 23264026)
Labcorp Genetics (formerly Invitae), Labcorp RCV000526404 SCV000622847 pathogenic Ataxia-telangiectasia syndrome 2024-01-28 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 292 of the ATM protein (p.Pro292Leu). This variant is present in population databases (rs747727055, gnomAD 0.005%). This missense change has been observed in individuals with severe combined immunodeficiency and A-T and a milder phenotype of ataxia telangiectasia (A-T) (PMID: 10873394, 18634022, 19431188, 23264026, 30549301). This variant is also known as 1260C>T. ClinVar contains an entry for this variant (Variation ID: 229794). 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: 18634022, 19431188). For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000526404 SCV000800812 likely pathogenic Ataxia-telangiectasia syndrome 2018-05-04 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000220769 SCV000910967 pathogenic Hereditary cancer-predisposing syndrome 2020-11-11 criteria provided, single submitter clinical testing This missense variant replaces proline with leucine at codon 292 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). Functional studies have shown instability and low-level expression of the mutant protein, and absent or reduced kinase activity, as well as high radiosensitivity after ionizing radiation exposure of cells carrying this variant (PMID 18634022, 19431188). This variant has been reported in individuals affected with classic or mild form of ataxia-telangiectasia (PMID: 10873394, 18634022, 23264026, 30549301) and in individuals affected with breast cancer (PMID: 32957588; Color internal data). This variant has been identified in 3/279556 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000255507 SCV001448023 likely pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV000526404 SCV002024403 likely pathogenic Ataxia-telangiectasia syndrome 2019-02-04 criteria provided, single submitter clinical testing
Baylor Genetics RCV003468983 SCV004212061 pathogenic Familial cancer of breast 2023-03-15 criteria provided, single submitter clinical testing
Myriad Genetics, Inc. RCV003468983 SCV004931295 likely pathogenic Familial cancer of breast 2024-01-11 criteria provided, single submitter clinical testing This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 10873394, 12552559, 21792198, 23264026]. Functional studies indicate this variant impacts protein function [PMID: 18634022, 19431188, 21792198].
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000526404 SCV005039716 pathogenic Ataxia-telangiectasia syndrome 2024-03-19 criteria provided, single submitter clinical testing Variant summary: ATM c.875C>T (p.Pro292Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.1e-06 in 248178 control chromosomes. c.875C>T has been reported in the literature in multiple individuals affected with Ataxia-Telangiectasia (eg: Mitui_2009, Schon_2019, Reiman_2011, Jackson_2016). These data indicate that the variant is very likely to be associated with disease. Experimental evidence has shown the variant leads to reduced or absent ATM kinase activity (Barone_2009, Mitui_2009). The following publications have been ascertained in the context of this evaluation (PMID: 18634022, 30549301, 21792198, 26896183, 19431188). ClinVar contains an entry for this variant (Variation ID: 229794). Based on the evidence outlined above, the variant was classified as pathogenic.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000255507 SCV001742991 likely pathogenic not provided no assertion criteria provided clinical testing
Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences RCV001658022 SCV001877094 likely pathogenic Breast carcinoma no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000255507 SCV001955994 likely pathogenic not provided no assertion criteria provided clinical testing
Laboratory for Genotyping Development, RIKEN RCV003165551 SCV002758078 pathogenic Gastric cancer 2021-07-01 no assertion criteria provided research

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