11-94471601-G-C
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_ModerateBS2
The NM_005591.4(MRE11):c.818C>G(p.Ser273Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000115 in 1,612,526 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar 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 -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
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MRE11 | NM_005591.4 | c.818C>G | p.Ser273Cys | missense_variant | Exon 8 of 20 | ENST00000323929.8 | NP_005582.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MRE11 | ENST00000323929.8 | c.818C>G | p.Ser273Cys | missense_variant | Exon 8 of 20 | 1 | NM_005591.4 | ENSP00000325863.4 | ||
MRE11 | ENST00000323977.7 | c.818C>G | p.Ser273Cys | missense_variant | Exon 8 of 19 | 1 | ENSP00000326094.3 | |||
MRE11 | ENST00000407439.7 | c.827C>G | p.Ser276Cys | missense_variant | Exon 8 of 20 | 2 | ENSP00000385614.3 | |||
MRE11 | ENST00000393241.8 | c.818C>G | p.Ser273Cys | missense_variant | Exon 8 of 20 | 5 | ENSP00000376933.4 |
Frequencies
GnomAD3 genomes AF: 0.0000789 AC: 12AN: 152022Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000996 AC: 25AN: 250904Hom.: 0 AF XY: 0.000125 AC XY: 17AN XY: 135616
GnomAD4 exome AF: 0.000119 AC: 174AN: 1460504Hom.: 0 Cov.: 31 AF XY: 0.000128 AC XY: 93AN XY: 726560
GnomAD4 genome AF: 0.0000789 AC: 12AN: 152022Hom.: 0 Cov.: 32 AF XY: 0.0000539 AC XY: 4AN XY: 74262
ClinVar
Submissions by phenotype
not provided Uncertain:5
MRE11A has been only recently described in association with cancer predisposition and the risks are not well understood. This variant is denoted MRE11A c.818C>G at the cDNA level, p.Ser273Cys (S273C) at the protein level, and results in the change of a Serine to a Cysteine (TCT>TGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MRE11A Ser273Cys was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. This is a non-conservative amino acid substitution which is likely to impact secondary protein structure since Serine and Cysteine differ in size and/or other properties. MRE11A Ser273Cys occurs at a position that is highly conserved across species and is not located in a known functional domain. In silico analyses predict this variant is probably 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. -
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The MRE11 c.818C>G (p.Ser273Cys) variant has been reported in the published literature in breast cancer cases as well as in reportedly healthy individuals (see LOVD (http://databases.lovd.nl/shared/) and PMID: 33471991 (2021)). The frequency of this variant in the general population, 0.00017 (6/35362 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 damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -
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Ataxia-telangiectasia-like disorder 1 Uncertain:3
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This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
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not specified Uncertain:1
Variant summary: MRE11A c.818C>G (p.Ser273Cys) results in a non-conservative amino acid change located in the DNA double-strand break repair protein Mre11, N-terminal metallophosphatase domain (IPR041796) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 282264 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.818C>G has been reported in the literature in individuals affected with breast cancer or colorectal cancer without evidence for causality (e.g. VanMarcke_2020, Erdem_2020). These reports do not provide unequivocal conclusions about association of the variant with Ataxia Telangiectasia-Like Disorder. 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: 32283892, 32295625).ClinVar contains an entry for this variant (Variation ID: 127987). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Hereditary cancer-predisposing syndrome Uncertain:1
The p.S273C variant (also known as c.818C>G), located in coding exon 7 of the MRE11A gene, results from a C to G substitution at nucleotide position 818. The serine at codon 273 is replaced by cysteine, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Ovarian neoplasm Uncertain:1
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Ataxia-telangiectasia-like disorder Uncertain:1
This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 273 of the MRE11 protein (p.Ser273Cys). This variant is present in population databases (rs143400546, gnomAD 0.01%). 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: 127987). 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 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