rs375261439
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2
The NM_005591.4(MRE11):c.1462C>T(p.Arg488Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000675 in 1,613,930 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. R488G) has been classified as Uncertain significance.
Frequency
Consequence
NM_005591.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MRE11 | NM_005591.4 | c.1462C>T | p.Arg488Cys | missense_variant | 13/20 | ENST00000323929.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MRE11 | ENST00000323929.8 | c.1462C>T | p.Arg488Cys | missense_variant | 13/20 | 1 | NM_005591.4 | P3 | |
MRE11 | ENST00000323977.7 | c.1462C>T | p.Arg488Cys | missense_variant | 13/19 | 1 | |||
MRE11 | ENST00000407439.7 | c.1471C>T | p.Arg491Cys | missense_variant | 13/20 | 2 | |||
MRE11 | ENST00000393241.8 | c.1462C>T | p.Arg488Cys | missense_variant | 13/20 | 5 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000657 AC: 10AN: 152102Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000139 AC: 35AN: 251380Hom.: 0 AF XY: 0.000132 AC XY: 18AN XY: 135866
GnomAD4 exome AF: 0.0000677 AC: 99AN: 1461710Hom.: 0 Cov.: 31 AF XY: 0.0000770 AC XY: 56AN XY: 727158
GnomAD4 genome ? AF: 0.0000657 AC: 10AN: 152220Hom.: 0 Cov.: 32 AF XY: 0.0000940 AC XY: 7AN XY: 74434
ClinVar
Submissions by phenotype
Ataxia-telangiectasia-like disorder 1 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Jul 28, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Dec 22, 2021 | MRE11 NM_005591.4 exon 13 p.Arg488Cys (c.1462C>T): This variant has been observed in individuals in at least 10 individuals undergoing genetic testing for hereditary cancer predisposition (Couch 2015 PMID:25452441; Tsaousis 2019 PMID:31159747). It is present in 0.02% (26/129120) European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/11-94192612-G-A?dataset=gnomad_r2_1). This variant is present in ClinVar with classifications ranging from likely benign to VUS (Variation ID: 127972). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 23, 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneKor MSA | Aug 01, 2018 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 04, 2014 | MRE11A has been only recently described in association with cancer predisposition and the risks are not well understood. This variant is denoted MRE11A c.1462C>T at the cDNA level, p.Arg488Cys (R488C) at the protein level, and results in the change of an Arginine to a Cysteine (CGT>TGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MRE11A Arg488Cys was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. This variant is a non-conservative substitution in which a positive polar amino acid is replaced with a neutral polar one, altering a position that is highly conserved throughout evolution and is not located in a known functional domain. Multiple in silico algorithms predict that this variant may be damaging to protein structure and function. On a molecular level, the impact of this missense variant on protein structure and function is not known and thus we consider this to be a variant of uncertain significance. Furthermore, based on the currently available information, cancer risks associated with this variant, and the MRE11A gene, remain unclear. - |
Ataxia-telangiectasia-like disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 17, 2022 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 488 of the MRE11 protein (p.Arg488Cys). This variant is present in population databases (rs375261439, gnomAD 0.02%). This missense change has been observed in individual(s) with breast cancer and in individuals undergoing genetic testing for hereditary cancer predisposition (PMID: 25452441, 31159747). ClinVar contains an entry for this variant (Variation ID: 127972). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at