11-94471742-G-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM2BP4_ModerateBP6BS2

The NM_005591.4(MRE11):c.677C>G(p.Thr226Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,611,456 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T226I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

MRE11
NM_005591.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 9.77

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 Likely_benign. Variant got -5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.18452471).

BP6

Variant 11-94471742-G-C is Benign according to our data. Variant chr11-94471742-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 407892.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=2}.

BS2

High AC in GnomAdExome at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MRE11	NM_005591.4 linkuse as main transcript	c.677C>G	p.Thr226Ser	missense_variant	8/20	ENST00000323929.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MRE11	ENST00000323929.8 linkuse as main transcript	c.677C>G	p.Thr226Ser	missense_variant	8/20	1	NM_005591.4	P3	P49959-1
MRE11	ENST00000323977.7 linkuse as main transcript	c.677C>G	p.Thr226Ser	missense_variant	8/19	1			P49959-2
MRE11	ENST00000407439.7 linkuse as main transcript	c.686C>G	p.Thr229Ser	missense_variant	8/20	2			P49959-3
MRE11	ENST00000393241.8 linkuse as main transcript	c.677C>G	p.Thr226Ser	missense_variant	8/20	5		A1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151978

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:

0.000385

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000201

AC:

AN:

249362

Hom.:

AF XY:

0.00000741

AC XY:

AN XY:

134874

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000273

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1459360

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725966

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000505

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152096

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 07, 2023

The c.677C>G (p.T226S) alteration is located in exon 8 (coding exon 7) of the MRE11A gene. This alteration results from a C to G substitution at nucleotide position 677, causing the threonine (T) at amino acid position 226 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Ataxia-telangiectasia-like disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Apr 12, 2022

This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 226 of the MRE11 protein (p.Thr226Ser). This variant is present in population databases (rs201276188, gnomAD 0.02%). 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: 407892). 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. -

Ovarian cancer

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University

Jan 01, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.13

Cadd

Uncertain

Dann

Uncertain

0.99

DEOGEN2

Uncertain

0.53

D;.;.;.

Eigen

Uncertain

0.21

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.79

T;T;T;T

M_CAP

Benign

0.056

MetaRNN

Benign

0.18

T;T;T;T

MetaSVM

Benign

-0.29

MutationAssessor

Uncertain

2.1

M;.;M;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-2.1

N;N;N;N

REVEL

Uncertain

0.36

Sift

Uncertain

0.023

D;D;D;D

Sift4G

Benign

0.19

T;T;T;T

Polyphen

0.014

B;.;B;.

Vest4

0.39

MutPred

0.46

.;Gain of disorder (P = 0.0339);.;.;

MVP

0.71

MPC

0.091

ClinPred

0.33

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.59

gMVP

0.36

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