rs148637964

Positions:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

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).

Frequency

Genomes: 𝑓 0.00058 ( 1 hom., cov: 32)

Exomes 𝑓: 0.000053 ( 1 hom. )

Consequence

MRE11
NM_005591.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:3

Conservation

PhyloP100: 0.569

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.015012652).

BP6

Variant 11-94445866-C-G is Benign according to our data. Variant chr11-94445866-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127977.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=4, Likely_benign=3}.

BS2

High AC in GnomAd4 at 88 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MRE11	NM_005591.4 link	c.1811G>C	p.Arg604Pro	missense_variant	16/20	ENST00000323929.8	NP_005582.1	P49959-1A0A024R395

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MRE11	ENST00000323929.8 link	c.1811G>C	p.Arg604Pro	missense_variant	16/20	1	NM_005591.4	ENSP00000325863.4		P49959-1

Frequencies

GnomAD3 genomes

AF:

0.000572

AC:

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00205

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:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000116

AC:

AN:

250994

Hom.:

AF XY:

0.0000664

AC XY:

AN XY:

135622

show subpopulations

Gnomad AFR exome

AF:

0.00154

Gnomad AMR exome

AF:

0.0000868

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000534

AC:

AN:

1461482

Hom.:

Cov.:

AF XY:

0.0000426

AC XY:

AN XY:

727086

show subpopulations

Gnomad4 AFR exome

AF:

0.00161

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.000182

GnomAD4 genome

AF:

0.000578

AC:

AN:

152262

Hom.:

Cov.:

AF XY:

0.000551

AC XY:

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.00207

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:

0.0000147

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00000851

Hom.:

Bravo

AF:

0.000555

ExAC

AF:

0.000140

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 24, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 10, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 09, 2024	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 0.0001 in 1613744 control chromosomes, predominantly at a frequency of 0.0019 within the African or African-American subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 1.44 fold of the estimated maximal expected allele frequency for a pathogenic variant in MRE11A causing Ataxia Telangiectasia-Like Disorder phenotype (0.0013). To our knowledge, no occurrence of c.1811G>C in individuals affected with MRE11A-related conditions and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 127977). Based on the evidence outlined above, the variant was classified as likely benign. -

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	- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 02, 2024

In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Ataxia-telangiectasia-like disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

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, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 07, 2024

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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.26

CADD

Benign

8.3

DANN

Benign

0.85

DEOGEN2

Benign

0.091

T;.;.

Eigen

Benign

-0.94

Eigen_PC

Benign

-0.96

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.48

T;T;T

M_CAP

Benign

0.021

MetaRNN

Benign

0.015

T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

1.6

L;.;.

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.76

N;N;N

REVEL

Benign

0.21

Sift

Benign

0.065

T;T;T

Sift4G

Benign

0.064

T;T;T

Polyphen

0.0010

B;.;.

Vest4

0.20

MVP

0.46

MPC

0.12

ClinPred

0.0041

GERP RS

0.49

Varity_R

0.19

gMVP

0.50

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