11-94459433-G-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_005591.4(MRE11):c.1475C>A(p.Ala492Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00604 in 1,613,870 control chromosomes in the GnomAD database, including 47 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0039 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0063 ( 46 hom. )

Consequence

MRE11
NM_005591.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:15O:1

Conservation

PhyloP100: 4.87

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0070512593).

BP6

Variant 11-94459433-G-T is Benign according to our data. Variant chr11-94459433-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127031.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Benign=6, Uncertain_significance=3, not_provided=1}. Variant chr11-94459433-G-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.00626 (9149/1461648) while in subpopulation NFE AF= 0.0076 (8452/1111842). AF 95% confidence interval is 0.00747. There are 46 homozygotes in gnomad4_exome. There are 4322 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High AC in GnomAd4 at 596 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MRE11	NM_005591.4 link	c.1475C>A	p.Ala492Asp	missense_variant	Exon 13 of 20	ENST00000323929.8	NP_005582.1	P49959-1A0A024R395

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MRE11	ENST00000323929.8 link	c.1475C>A	p.Ala492Asp	missense_variant	Exon 13 of 20	1	NM_005591.4	ENSP00000325863.4	P49959-1
MRE11	ENST00000323977.7 link	c.1475C>A	p.Ala492Asp	missense_variant	Exon 13 of 19	1		ENSP00000326094.3	P49959-2
MRE11	ENST00000407439.7 link	c.1484C>A	p.Ala495Asp	missense_variant	Exon 13 of 20	2		ENSP00000385614.3	P49959-3
MRE11	ENST00000393241.8 link	c.1475C>A	p.Ala492Asp	missense_variant	Exon 13 of 20	5		ENSP00000376933.4	F8W7U8

Frequencies

GnomAD3 genomes

AF:

0.00392

AC:

596

AN:

152104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00121

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00537

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00666

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00345

AC:

867

AN:

251386

Hom.:

AF XY:

0.00316

AC XY:

430

AN XY:

135874

show subpopulations

Gnomad AFR exome

AF:

0.000738

Gnomad AMR exome

AF:

0.00489

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.000462

Gnomad NFE exome

AF:

0.00568

Gnomad OTH exome

AF:

0.00473

GnomAD4 exome

AF:

0.00626

AC:

9149

AN:

1461648

Hom.:

Cov.:

AF XY:

0.00594

AC XY:

4322

AN XY:

727140

show subpopulations

Gnomad4 AFR exome

AF:

0.00105

Gnomad4 AMR exome

AF:

0.00512

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000812

Gnomad4 FIN exome

AF:

0.000524

Gnomad4 NFE exome

AF:

0.00760

Gnomad4 OTH exome

AF:

0.00644

GnomAD4 genome

AF:

0.00392

AC:

596

AN:

152222

Hom.:

Cov.:

AF XY:

0.00349

AC XY:

260

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.00120

Gnomad4 AMR

AF:

0.00536

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000377

Gnomad4 NFE

AF:

0.00666

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00529

Hom.:

Bravo

AF:

0.00423

TwinsUK

AF:

0.00836

AC:

ALSPAC

AF:

0.00830

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00628

AC:

ExAC

AF:

0.00338

AC:

411

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00649

EpiControl

AF:

0.00599

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:15Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:5Other:1

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MRE11: BS2 -

Dec 14, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 28051113, 26898890, 26483394, 30666157) -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Harris Lab, University of Minnesota

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Ataxia-telangiectasia-like disorder 1

Uncertain:2Benign:2

Apr 27, 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 05, 2017

Counsyl

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 30, 2018

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Oct 14, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MRE11 c.1475C>A; p.Ala492Asp variant (rs61749249) is reported in the literature in individuals with hereditary breast and ovarian cancer syndrome, colon cancer, or pancreatic cancer (Caminsky 2016, Castellanos 2017, Hu 2016, Taghizadeh 2020). However, this variant is also found in the non-Finnish European population with an allele frequency of 0.56% (720/129116 alleles, including 3 homozygotes) in the Genome Aggregation Database. This variant is reported in the ClinVar database (Variation ID: 127031). The alanine at codon 492 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.234). Based on available information, the clinical significance of this variant is uncertain at this time. References: Caminsky NG et al. Prioritizing Variants in Complete Hereditary Breast and Ovarian Cancer Genes in Patients Lacking Known BRCA Mutations. Hum Mutat. 2016 Jul;37(7):640-52. PMID: 26898890 Castellanos E et al. A comprehensive custom panel design for routine hereditary cancer testing: preserving control, improving diagnostics and revealing a complex variation landscape. Sci Rep. 2017 Jan 4;7:39348. PMID: 28051113 Hu C et al. Prevalence of Pathogenic Mutations in Cancer Predisposition Genes among Pancreatic Cancer Patients. Cancer Epidemiol Biomarkers Prev. 2016 Jan;25(1):207-11. PMID: 26483394 Taghizadeh H et al. Applied precision medicine in metastatic pancreatic ductal adenocarcinoma. Ther Adv Med Oncol. 2020 Jul 10;12:1758835920938611. PMID: 32699558; -

not specified

Benign:4

Apr 25, 2016

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 22, 2021

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DNA sequence analysis of the MRE11A gene demonstrated a sequence change, c.1475C>A, in exon 13 that results in an amino acid change, p.Ala492Asp. This sequence change does not appear to have been previously described in patients with MRE11A-related disorders and has been described in the gnomAD database with a reatively high frequency of 0.56% in the European sub-population (dbSNP rs61749249). The p.Ala492Asp change affects a moderately conserved amino acid residue located in a domain of the MRE11A protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Ala492Asp substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Ala492Asp change remains unknown at this time. -

Jan 25, 2024

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 06, 2020

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:2

Oct 19, 2020

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Aug 07, 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. -

Hereditary breast ovarian cancer syndrome

Benign:1

Apr 19, 2022

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Ataxia-telangiectasia-like disorder

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.15

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.16

T;.;.;.

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.65

T;T;T;T

M_CAP

Benign

0.055

MetaRNN

Benign

0.0071

T;T;T;T

MetaSVM

Benign

-0.42

MutationAssessor

Uncertain

2.5

M;.;M;.

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-2.1

N;N;N;N

REVEL

Benign

0.23

Sift

Benign

0.12

T;T;T;T

Sift4G

Benign

0.25

T;T;T;T

Polyphen

0.95

P;.;D;.

Vest4

0.58

MVP

0.78

MPC

0.32

ClinPred

0.054

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.35

gMVP

0.41

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