ClinVar Miner

Submissions for variant NM_005591.4(MRE11):c.1643T>C (p.Ile548Thr)

gnomAD frequency: 0.00016  dbSNP: rs373522639
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131733 SCV000186774 uncertain significance Hereditary cancer-predisposing syndrome 2022-09-30 criteria provided, single submitter clinical testing The p.I548T variant (also known as c.1643T>C), located in coding exon 14 of the MRE11A gene, results from a T to C substitution at nucleotide position 1643. The isoleucine at codon 548 is replaced by threonine, an amino acid with similar properties. 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.
Invitae RCV000627772 SCV000254854 likely benign Ataxia-telangiectasia-like disorder 2024-01-31 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000518010 SCV000614121 uncertain significance not provided 2023-06-19 criteria provided, single submitter clinical testing Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity (http://gnomad.broadinstitute.org). Computational tools predict that this variant is not damaging.
Illumina Laboratory Services, Illumina RCV001113939 SCV001271755 uncertain significance Ataxia-telangiectasia-like disorder 1 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Baylor Genetics RCV001113939 SCV001481460 uncertain significance Ataxia-telangiectasia-like disorder 1 2020-05-13 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Sema4, Sema4 RCV000131733 SCV002538398 uncertain significance Hereditary cancer-predisposing syndrome 2021-05-17 criteria provided, single submitter curation
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV001113939 SCV003920214 uncertain significance Ataxia-telangiectasia-like disorder 1 2021-03-30 criteria provided, single submitter clinical testing MRE11 NM_005591.3 exon 15 p.Ile548Thr (c.1643T>C): This variant has not been reported in the literature but is present in 0.01% (24/128966) of European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/11-94180525-A-G?dataset=gnomad_r2_1). This variant is present in ClinVar (Variation ID:142542). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003323411 SCV004028945 likely benign not specified 2023-07-21 criteria provided, single submitter clinical testing Variant summary: MRE11 c.1643T>C (p.Ile548Thr) results in a non-conservative amino acid change in 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-05 in 251232 control chromosomes. The observed variant frequency is approximately 1.3 fold of the estimated maximal expected allele frequency for a pathogenic variant in MRE11 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (6.3e-05), strongly suggesting that the variant is benign. c.1643T>C has been reported in the literature as a VUS in settings of multigene panel testing in at least one individual with a personal and/or family history of cancer reportedly tested negative on routine BRCA analysis (e.g., Nunziato_2022). However, this report does not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 36035419). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Six submitters classifieid it as a variant of uncertain significance, while one submitter classified it as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000518010 SCV004220914 uncertain significance not provided 2023-06-19 criteria provided, single submitter clinical testing In the published literature, this variant has been reported in an individual with personal and/or family history of breast cancer (PMID: 36035419 (2022)). In a large-scale breast cancer association study, this variant was observed in individuals with breast cancer as well as in unaffected control individuals (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/)). The frequency of this variant in the general population, 0.00019 (24/128966 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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.

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