rs587782742

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

The NM_005591.4(MRE11):c.826C>T(p.Pro276Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000372 in 1,612,230 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P276A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

MRE11
NM_005591.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

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 Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MRE11	NM_005591.4 linkuse as main transcript	c.826C>T	p.Pro276Ser	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.826C>T	p.Pro276Ser	missense_variant	8/20	1	NM_005591.4	P3	P49959-1
MRE11	ENST00000323977.7 linkuse as main transcript	c.826C>T	p.Pro276Ser	missense_variant	8/19	1			P49959-2
MRE11	ENST00000407439.7 linkuse as main transcript	c.835C>T	p.Pro279Ser	missense_variant	8/20	2			P49959-3
MRE11	ENST00000393241.8 linkuse as main transcript	c.826C>T	p.Pro276Ser	missense_variant	8/20	5		A1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151884

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000797

AC:

AN:

250784

Hom.:

AF XY:

0.00000738

AC XY:

AN XY:

135590

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000404

AC:

AN:

1460346

Hom.:

Cov.:

AF XY:

0.0000372

AC XY:

AN XY:

726490

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000477

Gnomad4 OTH exome

AF:

0.0000829

GnomAD4 genome

AF:

0.00000658

AC:

AN:

151884

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74176

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000283

Hom.:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000546

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

May 22, 2019

- -

Hereditary cancer-predisposing syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 27, 2023

The p.P276S variant (also known as c.826C>T), located in coding exon 7 of the MRE11A gene, results from a C to T substitution at nucleotide position 826. The proline at codon 276 is replaced by serine, an amino acid with similar properties. This variant was reported in 1/1824 patients with triple negative breast cancer, who were unselected for family history of breast or ovarian cancer (Couch FJ et al. J. Clin. Oncol. 2015 Feb;33:304-11). This alteration was also reported in a study of 1297 cases of early-onset breast cancer and 1121 controls (Young EL et al. J. Med. Genet. 2016 Jun;53:366-76). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Ataxia-telangiectasia-like disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 07, 2022

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 276 of the MRE11 protein (p.Pro276Ser). This variant is present in population databases (rs587782742, gnomAD 0.002%). This missense change has been observed in individual(s) with breast cancer (PMID: 25452441). ClinVar contains an entry for this variant (Variation ID: 142818). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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

0.15

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.020

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Benign

0.26

T;.;.;.

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

D;D;D;D

M_CAP

Benign

0.073

MetaRNN

Uncertain

0.63

D;D;D;D

MetaSVM

Uncertain

0.38

MutationAssessor

Uncertain

2.5

M;.;M;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.73

PROVEAN

Uncertain

-2.7

D;D;N;D

REVEL

Uncertain

0.63

Sift

Uncertain

0.0040

D;D;D;D

Sift4G

Benign

0.075

T;T;T;T

Polyphen

1.0

D;.;D;.

Vest4

0.63

MutPred

0.56

.;Gain of MoRF binding (P = 0.0604);.;.;

MVP

0.79

MPC

0.088

ClinPred

0.81

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.31

gMVP

0.58

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