rs148637964
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_005591.4(MRE11):c.1811G>C(p.Arg604Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000103 in 1,613,744 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. 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. R604H) has been classified as Uncertain significance.
Frequency
Consequence
NM_005591.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MRE11 | NM_005591.4 | c.1811G>C | p.Arg604Pro | missense_variant | 16/20 | ENST00000323929.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MRE11 | ENST00000323929.8 | c.1811G>C | p.Arg604Pro | missense_variant | 16/20 | 1 | NM_005591.4 | P3 |
Frequencies
GnomAD3 genomes AF: 0.000572 AC: 87AN: 152144Hom.: 1 Cov.: 32
GnomAD3 exomes AF: 0.000116 AC: 29AN: 250994Hom.: 0 AF XY: 0.0000664 AC XY: 9AN XY: 135622
GnomAD4 exome AF: 0.0000534 AC: 78AN: 1461482Hom.: 1 Cov.: 30 AF XY: 0.0000426 AC XY: 31AN XY: 727086
GnomAD4 genome AF: 0.000578 AC: 88AN: 152262Hom.: 1 Cov.: 32 AF XY: 0.000551 AC XY: 41AN XY: 74462
ClinVar
Submissions by phenotype
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jan 24, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 27, 2018 | Variant summary: MRE11A c.1811G>C (p.Arg604Pro) 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 0.00022 in 276718 control chromosomes. The observed variant frequency is approximately 3.5 fold of the estimated maximal expected allele frequency for a pathogenic variant in MRE11A causing Hereditary Breast and Ovarian Cancer phenotype (6.3e-05), suggesting that the variant is benign. However, due to potential pseudogen interference, this data must be interpreted with caution. To our knowledge, no occurrence of c.1811G>C in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as VUS - possibly benign. - |
not provided Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jan 09, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 29, 2013 | MRE11A, which is involved in DNA damage repair, has been only recently described in association with cancer predisposition and the risks are not well understood.This variant is denoted MRE11A c.1811G>C at the cDNA level, p.Arg604Pro (R604P) at the protein level, and results in the change of an Arginine to a Proline (CGT>CCT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MRE11A Arg604Pro was observed at an allele frequency of 0.1% in 1000 Genomes (0.4% among individuals of African ancestry.) This variant is a non-conservative amino acid substitution, altering a position that is well conserved throughout evolution and is not located in a known functional domain. In silico analyses predict this variant to have a benign effect on 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. - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 30, 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 | curation | Sema4, Sema4 | Sep 10, 2021 | - - |
Ataxia-telangiectasia-like disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 12, 2024 | This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 604 of the MRE11 protein (p.Arg604Pro). This variant is present in population databases (rs148637964, gnomAD 0.1%), including at least one homozygous and/or hemizygous individual. This variant has not been reported in the literature in individuals affected with MRE11-related conditions. ClinVar contains an entry for this variant (Variation ID: 127977). 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 tolerated. 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. - |
MRE11-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 19, 2023 | The MRE11 c.1811G>C variant is predicted to result in the amino acid substitution p.Arg604Pro. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.15% of alleles in individuals of African descent in gnomAD, including one homozygous individual and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/127977/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at