rs372068015
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP5BS2
The NM_005591.4(MRE11):c.77T>C(p.Met26Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000176 in 1,595,380 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. M26L) has been classified as Uncertain significance.
Frequency
Consequence
NM_005591.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MRE11 | NM_005591.4 | c.77T>C | p.Met26Thr | missense_variant | 3/20 | ENST00000323929.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MRE11 | ENST00000323929.8 | c.77T>C | p.Met26Thr | missense_variant | 3/20 | 1 | NM_005591.4 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152226Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251142Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135776
GnomAD4 exome AF: 0.0000187 AC: 27AN: 1443154Hom.: 0 Cov.: 28 AF XY: 0.0000222 AC XY: 16AN XY: 719132
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152226Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74378
ClinVar
Submissions by phenotype
Ataxia-telangiectasia-like disorder 1 Pathogenic:1Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 20, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | 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. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München | Jun 13, 2019 | - - |
not provided Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2020 | - - |
Ataxia-telangiectasia-like disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 04, 2023 | This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 26 of the MRE11 protein (p.Met26Thr). This variant is present in population databases (rs372068015, gnomAD 0.005%). This missense change has been observed in individual(s) with ataxia-telangiectasia, abnormalities of the nervous system, generalized combined dystonia and ovarian cancer (PMID: 26633542, 28849312, 30441849, 33098801; Invitae; external communication). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 182553). 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. 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. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 05, 2023 | Variant summary: MRE11 c.77T>C (p.Met26Thr) results in a non-conservative amino acid change located in the Calcineurin-like phosphoesterase domain, ApaH type (IPR004843) of 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 2e-05 in 251142 control chromosomes (gnomAD). c.77T>C has been reported in the literature in an individual affected with an abnormality of the nervous system (Retterer_2016) and another with dystonia who had a pathogenic variant in trans (Zech_2017, 2020). These data indicate that the variant may be associated with disease in the context of Ataxia Telangiectasia-Like Disorder. Co-occurrence with another pathogenic variant has been reported (BRCA2 c.5946del, p.Ser1982fs, internal database), providing supporting evidence for a benign role in the context of Hereditary Breast and Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33098801, 26633542, 28849312). Six submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and classified it as uncertain significance (n=3) or likely pathogenic (n=3). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 22, 2023 | 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), and was detected in an individual with nervous system abnormalities who underwent whole exome sequencing (Retterer K et al. Genet Med, 2016 07;18:696-704). This variant was also reported in 12/60,466 breast cancer cases and in 5/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at