11-94447240-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_005591.4(MRE11):​c.1762G>A​(p.Gly588Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G588E) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Consequence

MRE11
NM_005591.4 missense

Scores

1
3
15

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 2.71
Variant links:
Genes affected
MRE11 (HGNC:7230): (MRE11 homolog, double strand break repair nuclease) This gene encodes a nuclear protein involved in homologous recombination, telomere length maintenance, and DNA double-strand break repair. By itself, the protein has 3' to 5' exonuclease activity and endonuclease activity. The protein forms a complex with the RAD50 homolog; this complex is required for nonhomologous joining of DNA ends and possesses increased single-stranded DNA endonuclease and 3' to 5' exonuclease activities. In conjunction with a DNA ligase, this protein promotes the joining of noncomplementary ends in vitro using short homologies near the ends of the DNA fragments. This gene has a pseudogene on chromosome 3. Alternative splicing of this gene results in two transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.2281053).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MRE11NM_005591.4 linkuse as main transcriptc.1762G>A p.Gly588Arg missense_variant 15/20 ENST00000323929.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MRE11ENST00000323929.8 linkuse as main transcriptc.1762G>A p.Gly588Arg missense_variant 15/201 NM_005591.4 P3P49959-1

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
31
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJun 10, 2023The p.G588R variant (also known as c.1762G>A), located in coding exon 14 of the MRE11A gene, results from a G to A substitution at nucleotide position 1762. The glycine at codon 588 is replaced by arginine, 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 tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Ataxia-telangiectasia-like disorder Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeApr 28, 2023In 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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 479770). This variant has not been reported in the literature in individuals affected with MRE11-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 588 of the MRE11 protein (p.Gly588Arg). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.22
BayesDel_addAF
Benign
0.0097
T
BayesDel_noAF
Benign
-0.22
CADD
Benign
18
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.30
T;.;.;.
Eigen
Benign
-0.014
Eigen_PC
Benign
0.13
FATHMM_MKL
Uncertain
0.90
D
LIST_S2
Benign
0.85
T;T;T;T
M_CAP
Benign
0.039
D
MetaRNN
Benign
0.23
T;T;T;T
MetaSVM
Benign
-0.50
T
MutationAssessor
Uncertain
2.5
M;.;M;.
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Benign
0.41
T
PROVEAN
Benign
-1.6
N;N;N;N
REVEL
Benign
0.15
Sift
Uncertain
0.025
D;D;D;D
Sift4G
Benign
0.070
T;T;T;T
Polyphen
0.018
B;.;B;.
Vest4
0.26
MutPred
0.26
.;Gain of methylation at G591 (P = 0.0144);.;.;
MVP
0.77
MPC
0.11
ClinPred
0.90
D
GERP RS
5.2
Varity_R
0.10
gMVP
0.38

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1555005282; hg19: chr11-94180406; COSMIC: COSV60577645; API