ClinVar Miner

Submissions for variant NM_005591.3(MRE11):c.77T>C (p.Met26Thr) (rs372068015)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000160576 SCV000218111 uncertain significance Hereditary cancer-predisposing syndrome 2020-05-13 criteria provided, single submitter clinical testing The p.M26T variant (also known as c.77T>C), located in coding exon 2 of the MRE11A gene, results from a T to C substitution at nucleotide position 77. The methionine at codon 26 is replaced by threonine, an amino acid with similar properties. This alteration has been detected in trans with a second pathogenic mutation in MRE11A in an individual with combined dystonia (Zech M et al. Neurogenetics, 2017 Dec;18:195-205). 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 RCV001034631 SCV000288950 likely pathogenic Ataxia-telangiectasia-like disorder 2020-01-10 criteria provided, single submitter clinical testing This sequence change replaces methionine with threonine at codon 26 of the MRE11 protein (p.Met26Thr). The methionine residue is weakly conserved and there is a moderate physicochemical difference between methionine and threonine. This variant is present in population databases (rs372068015, ExAC 0.002%). This variant has been reported to segregate in a family with two individuals affected with a phenotype consistent with ataxia-telangiectasia. Both individuals carried a second MRE11 pathogenic allele, in trans with this missense mutation (Invitae, external communication). This variant has also been reported in an individual affected with abnormalities of the nervous system (PMID: 26633542), in combination with another MRE11 pathogenic allele in an individual with childhood-onset generalized combined dystonia (PMID: 28849312), and in an individual with ovarian cancer (PMID: 30441849). ClinVar contains an entry for this variant (Variation ID: 182553). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: Tolerated; PolyPhen-2: Possibly Damaging; Align-GVGD: Class C0). 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.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000761799 SCV000891996 likely pathogenic not provided 2020-11-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000684815 SCV001271865 uncertain significance Ataxia-telangiectasia-like disorder 1 2018-01-12 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.
Institute of Human Genetics, Klinikum rechts der Isar RCV000684815 SCV001150167 likely pathogenic Ataxia-telangiectasia-like disorder 1 2019-06-13 no assertion criteria provided clinical testing

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