11-94420176-A-T

Position:

chr11-94420176-A-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_005591.4(MRE11):c.2076T>A(p.Asp692Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000259 in 1,584,400 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000026 ( 0 hom. )

Consequence

MRE11
NM_005591.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: -3.04

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]

MRE11 links:

MRE11 (HGNC:):

MRE11 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.035371542).

BS2

High AC in GnomAdExome4 at 37 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MRE11	NM_005591.4 linkuse as main transcript	c.2076T>A	p.Asp692Glu	missense_variant	20/20	ENST00000323929.8	NP_005582.1	P49959-1A0A024R395

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
MRE11	ENST00000323929.8 linkuse as main transcript	c.2076T>A	p.Asp692Glu	missense_variant	20/20	1	NM_005591.4	ENSP00000325863.4	P49959-1
MRE11	ENST00000323977.7 linkuse as main transcript	c.1992T>A	p.Asp664Glu	missense_variant	19/19	1		ENSP00000326094.3	P49959-2
MRE11	ENST00000407439.7 linkuse as main transcript	c.2085T>A	p.Asp695Glu	missense_variant	20/20	2		ENSP00000385614.3	P49959-3
MRE11	ENST00000393241.8 linkuse as main transcript	c.2073T>A	p.Asp691Glu	missense_variant	20/20	5		ENSP00000376933.4	F8W7U8

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000123

AC:

AN:

242970

Hom.:

AF XY:

0.00000757

AC XY:

AN XY:

132136

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000654

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000903

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000258

AC:

AN:

1432182

Hom.:

Cov.:

AF XY:

0.0000252

AC XY:

AN XY:

714054

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000140

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000174

Gnomad4 OTH exome

AF:

0.0000336

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152218

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.000478

Bravo

AF:

0.0000227

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000547

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Ataxia-telangiectasia-like disorder 1

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 26, 2019	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
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. -

Hereditary cancer-predisposing syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 07, 2023	The p.D692E variant (also known as c.2076T>A), located in coding exon 19 of the MRE11A gene, results from a T to A substitution at nucleotide position 2076. The aspartic acid at codon 692 is replaced by glutamic acid, an amino acid with highly similar properties. This alteration was detected in a cohort of 122 BRCA1/2-negative patients who underwent multi-gene panel testing for hereditary cancer (Yadav S et al. Fam. Cancer. 2017 07;16:319-328). This alteration was also reported in 1/1197 individuals from Greece, Romania, and Turkey undergoing evaluation for inherited cancer predisposition (Tsaousis G et al. BMC Cancer 2019 Jun;19(1):535). This amino acid position is highly 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. -
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

May 29, 2024

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign in association with a MRE11-related ataxia-telangiectasia-like disorder to our knowledge; This variant is associated with the following publications: (PMID: 27878467, 31159747) -

Ataxia-telangiectasia-like disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 01, 2021

This sequence change replaces aspartic acid with glutamic acid at codon 692 of the MRE11 protein (p.Asp692Glu). The aspartic acid residue is weakly conserved and there is a small physicochemical difference between aspartic acid and glutamic acid. This variant is present in population databases (rs778093337, ExAC 0.002%). This missense change has been observed in individual(s) with personal or family history of breast and/or ovarian cancer (PMID: 27878467, 31159747). ClinVar contains an entry for this variant (Variation ID: 184593). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.40

CADD

Benign

0.0040

DANN

Benign

0.60

DEOGEN2

Benign

0.067

T;.;.;.

Eigen

Benign

-2.3

Eigen_PC

Benign

-2.4

FATHMM_MKL

Benign

0.010

LIST_S2

Benign

0.59

T;T;T;T

M_CAP

Benign

0.053

MetaRNN

Benign

0.035

T;T;T;T

MetaSVM

Benign

-0.43

MutationAssessor

Benign

1.0

L;.;.;.

PrimateAI

Benign

0.47

PROVEAN

Benign

-0.16

N;N;N;N

REVEL

Benign

0.26

Sift

Benign

0.059

T;T;T;T

Sift4G

Benign

0.46

T;T;T;T

Polyphen

0.018

B;.;P;.

Vest4

0.23

MutPred

0.077

.;Loss of stability (P = 0.1798);.;.;

MVP

0.40

MPC

0.082

ClinPred

0.060

GERP RS

-11

Varity_R

0.044

gMVP

0.070

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over