Genetic Variant NM_005591.4:c.2092A>G (chr11-94420160-T-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_005591.4(MRE11):c.2092A>G(p.Met698Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000993 in 1,582,312 control chromosomes in the GnomAD database, including 25 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M698L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0055 ( 14 hom., cov: 33)

Exomes 𝑓: 0.00051 ( 11 hom. )

Consequence

MRE11
NM_005591.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: 2.02

Publications

9 publications found

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 Gene-Disease associations (from GenCC):

ataxia-telangiectasia-like disorder 1
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet, Ambry Genetics
breast cancer
Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics
familial ovarian cancer
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
hereditary breast carcinoma
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
prostate cancer
Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics

MRE11 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0042666793).

BP6

Variant 11-94420160-T-C is Benign according to our data. Variant chr11-94420160-T-C is described in ClinVar as Benign. ClinVar VariationId is 129622.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00549 (836/152340) while in subpopulation AFR AF = 0.0192 (799/41578). AF 95% confidence interval is 0.0181. There are 14 homozygotes in GnomAd4. There are 368 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 14 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005591.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MRE11	NM_005591.4	MANE Select	c.2092A>G	p.Met698Val	missense	Exon 20 of 20	NP_005582.1
MRE11	NM_001440460.1		c.2143A>G	p.Met715Val	missense	Exon 21 of 21	NP_001427389.1
MRE11	NM_001440461.1		c.2143A>G	p.Met715Val	missense	Exon 21 of 21	NP_001427390.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MRE11	ENST00000323929.8	TSL:1 MANE Select	c.2092A>G	p.Met698Val	missense	Exon 20 of 20	ENSP00000325863.4
MRE11	ENST00000323977.7	TSL:1	c.2008A>G	p.Met670Val	missense	Exon 19 of 19	ENSP00000326094.3
MRE11	ENST00000407439.7	TSL:2	c.2101A>G	p.Met701Val	missense	Exon 20 of 20	ENSP00000385614.3

Frequencies

GnomAD3 genomes

AF:

0.00545

AC:

829

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0191

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00144

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:

0.000103

Gnomad OTH

AF:

0.00382

GnomAD2 exomes

AF:

0.00144

AC:

353

AN:

244464

AF XY:

0.00100

show subpopulations

Gnomad AFR exome

AF:

0.0190

Gnomad AMR exome

AF:

0.000955

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000541

Gnomad OTH exome

AF:

0.000825

GnomAD4 exome

AF:

0.000514

AC:

735

AN:

1429972

Hom.:

Cov.:

AF XY:

0.000439

AC XY:

313

AN XY:

713102

show subpopulations

African (AFR)

AF:

0.0181

AC:

594

AN:

32838

American (AMR)

AF:

0.000786

AC:

AN:

44542

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25860

East Asian (EAS)

AF:

0.00

AC:

AN:

39320

South Asian (SAS)

AF:

0.000117

AC:

AN:

85650

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47324

Middle Eastern (MID)

AF:

0.000176

AC:

AN:

5694

European-Non Finnish (NFE)

AF:

0.00000734

AC:

AN:

1089408

Other (OTH)

AF:

0.00147

AC:

AN:

59336

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.424

Heterozygous variant carriers

125

156

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00549

AC:

836

AN:

152340

Hom.:

Cov.:

AF XY:

0.00494

AC XY:

368

AN XY:

74504

show subpopulations

African (AFR)

AF:

0.0192

AC:

799

AN:

41578

American (AMR)

AF:

0.00144

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

68020

Other (OTH)

AF:

0.00378

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

116

154

193

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00198

Hom.:

Bravo

AF:

0.00628

ESP6500AA

AF:

0.0164

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00154

AC:

187

Asia WGS

AF:

0.00376

AC:

AN:

3474

EpiCase

AF:

0.0000546

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Oct 25, 2013

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed.

Dec 07, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Aug 13, 2018

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: MRE11A c.2092A>G (p.Met698Val) results in a conservative amino acid change in the encoded protein sequence that is located outside of any known functional domains. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0019 in 270304 control chromosomes, predominantly within the African subpopulation at a frequency of 0.019, including 7 homozygotes in the gnomAD database. The observed variant frequency within African control individuals in the gnomAD database is approximately 300 fold of the estimated maximal expected allele frequency for a pathogenic variant in MRE11A causing Hereditary Breast and Ovarian Cancer phenotype (6.3e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African origin. Moreover, the variant was found in 76/2559 African American women (with 1 homozygote), who are older than age 70 years, and who have never had cancer (in the FLOSSIES database). To our knowledge, no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both laboratories classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign.

Ataxia-telangiectasia-like disorder 1

Benign:4

May 28, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jun 08, 2016

Counsyl

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

not provided

Benign:2

Oct 25, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Aug 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

MRE11: BP4, BS1, BS2

Hereditary cancer-predisposing syndrome

Benign:1

Nov 24, 2014

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as 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.

Ataxia-telangiectasia-like disorder

Benign:1

Jan 18, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Hereditary breast ovarian cancer syndrome

Benign:1

Apr 19, 2022

National Health Laboratory Service, Universitas Academic Hospital and University of the Free State

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.33

CADD

Benign

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.081

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.18

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.62

MetaRNN

Benign

0.0043

MetaSVM

Benign

-0.92

MutationAssessor

Benign

1.9

PhyloP100

2.0

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.43

REVEL

Benign

0.13

Sift

Uncertain

0.021

Sift4G

Benign

0.66

Polyphen

0.011

Vest4

0.39

MVP

0.57

MPC

0.087

ClinPred

0.014

GERP RS

3.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.26

gMVP

0.12

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over