rs371077728

chr11-94467821-G-Achr11-94467821-G-Cchr11-94467821-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 16P and 4B. PVS1PP5_Very_StrongBS2

The NM_005591.4(MRE11):c.1090C>T(p.Arg364Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000496 in 1,611,580 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R364R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000052 ( 0 hom. )

Consequence

MRE11
NM_005591.4 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 3.00

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 Pathogenic. Variant got 12 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 11-94467821-G-A is Pathogenic according to our data. Variant chr11-94467821-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 140953.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAdExome at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MRE11	NM_005591.4 linkuse as main transcript	c.1090C>T	p.Arg364Ter	stop_gained	10/20	ENST00000323929.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MRE11	ENST00000323929.8 linkuse as main transcript	c.1090C>T	p.Arg364Ter	stop_gained	10/20	1	NM_005591.4	P3	P49959-1
MRE11	ENST00000323977.7 linkuse as main transcript	c.1090C>T	p.Arg364Ter	stop_gained	10/19	1			P49959-2
MRE11	ENST00000407439.7 linkuse as main transcript	c.1099C>T	p.Arg367Ter	stop_gained	10/20	2			P49959-3
MRE11	ENST00000393241.8 linkuse as main transcript	c.1090C>T	p.Arg364Ter	stop_gained	10/20	5		A1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152048

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000946

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000517

AC:

AN:

251384

Hom.:

AF XY:

0.0000810

AC XY:

AN XY:

135858

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.000261

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000521

AC:

AN:

1459532

Hom.:

Cov.:

AF XY:

0.0000565

AC XY:

AN XY:

726252

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000505

Gnomad4 SAS exome

AF:

0.000186

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000504

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152048

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74264

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.0000656

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000946

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000340

Hom.:

Bravo

AF:

0.0000264

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Ataxia-telangiectasia-like disorder 1

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Aug 03, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 20, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	Feb 01, 2023	The inherited c.1090C>T, p.(Arg364Ter) variant identified in the MRE11 gene is a nonsense variant leading to the premature termination of the protein at amino acid 364/709 (exon 10/20), and is expected to undergo nonsense mediated decay. This variant occurs upstream of the Helix-Loop-Helix and GAR domains of MRE11 which include regions that are critical for both RAD50 and DNA binding (for Review, [PMID:36358700]). This variant is found with low frequency in population databases (gnomADv3.1.2, gnomADv2.1.1, BRAVO-TOPMed and All of Us) with highest allele frequency of 5.2e-5 (14 heterozygotes; 0 homozygotes, gnomADv2.1.1). The c.1090C>T, p.(Arg364Ter) variant is reported in ClinVar as Pathogenic (VarID:140953; 2 stars, 5 submissions, no conflicts) and has been reported in the literature in individuals with hereditary cancer predisposition [PMID:24763289, 25503501, 27153395, 28559769]. Additional nonsense and frameshift variants downstream of the one identified here have also been reported in ClinVar as Pathogenic (VarIDs:8782, 1681558, 820257, 481748, others), and reported in individuals with Ataxia-Telangiectasia-like Disorder [PMID:33426167, 11371508]. The inherited c.1090C>T, p.(Arg364Ter) variant identified in the MRE11 gene is reported here as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 09, 2019	- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Aug 01, 2019

- -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 12, 2022

The p.R364* pathogenic mutation (also known as c.1090C>T), located in coding exon 9 of the MRE11A gene, results from a C to T substitution at nucleotide position 1090. This changes the amino acid from an arginine to a stop codon within coding exon 9. This mutation was reported in an individual with a personal and family history breast cancer (Maxwell KN et al. Genet. Med. 2015 Aug; 17(8):630-8). This mutation, designated p.Arg364Ter, was also identified in an Asian Indian woman with breast cancer and a family history of breast and endometrial cancers (Sharma Bhai P et al. Breast Care (Basel), 2017 May;12:114-116). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Hereditary breast ovarian cancer syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Dec 05, 2022

Variant summary: MRE11 c.1090C>T (p.Arg364X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 5.2e-05 in 251384 control chromosomes (gnomAD). This frequency is not higher than the estimated maximum expected for a pathogenic variant in MRE11 causing Hereditary Breast and Ovarian Cancer (HBOC) Syndrome (6.3e-05). The variant, c.1090C>T, has been reported in the literature in several individuals affected with HBOC and other tumor phenotypes (e.g. LaDuca_2014, Sharma Bhai_2017, Maxwell_2017, Hartman_2020, Zhou_2020, and Walsh_2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Ataxia-telangiectasia-like disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 21, 2024

This sequence change creates a premature translational stop signal (p.Arg364*) in the MRE11 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MRE11 are known to be pathogenic (PMID: 23080121, 23912341). This variant is present in population databases (rs371077728, gnomAD 0.03%). This premature translational stop signal has been observed in individual(s) with hereditary cancer (PMID: 24763289). ClinVar contains an entry for this variant (Variation ID: 140953). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.60

Cadd

Pathogenic

Dann

Uncertain

1.0

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Uncertain

0.94

MutationTaster

Benign

1.0

A;A;A;A

Vest4

0.99

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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