11-94447288-G-A

Position:

chr11-94447288-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The ENST00000323929.8(MRE11):c.1714C>T(p.Arg572Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000936 in 1,613,564 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 Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R572R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000096 ( 0 hom. )

Consequence

MRE11
ENST00000323929.8 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 6.45

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 16 ACMG points.

PVS1

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

PP5

Variant 11-94447288-G-A is Pathogenic according to our data. Variant chr11-94447288-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 8784.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MRE11	NM_005591.4 linkuse as main transcript	c.1714C>T	p.Arg572Ter	stop_gained	15/20	ENST00000323929.8	NP_005582.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MRE11	ENST00000323929.8 linkuse as main transcript	c.1714C>T	p.Arg572Ter	stop_gained	15/20	1	NM_005591.4	ENSP00000325863	P3	P49959-1

Frequencies

GnomAD3 genomes

AF:

0.0000659

AC:

AN:

151776

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000485

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:

0.000118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000597

AC:

AN:

251278

Hom.:

AF XY:

0.0000663

AC XY:

AN XY:

135796

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:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000114

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000965

AC:

141

AN:

1461788

Hom.:

Cov.:

AF XY:

0.000100

AC XY:

AN XY:

727196

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000123

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000659

AC:

AN:

151776

Hom.:

Cov.:

AF XY:

0.0000540

AC XY:

AN XY:

74084

show subpopulations

Gnomad4 AFR

AF:

0.0000485

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:

0.000118

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000167

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.0000741

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Ataxia-telangiectasia-like disorder 1

Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	May 15, 2001	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Oct 22, 2018	The MRE11A c.1714C>T (p.Arg572Ter) variant is a stop-gained variant predicted to cause a premature truncation of the protein. The p.Arg572Ter variant has been reported in at least two studies in which it is found in a compound heterozygous state in two pairs of siblings from two families with ataxia-telangiectasia-like disorder (Pitts et al. 2001; Delia et al. 2004; Federighi et al. 2017). Control data are unavailable for this variant, which is reported at a frequency of 0.00013 in the European (non-Finnish) population of the Exome Aggregation Consortium. The p.Arg572Ter variant protein could not be detected in proband cells due to destabilisation of the variant by nonsense-mediated mRNA decay. In addition, functional assays in patient lymphoblastoid cell lines demonstrated that the p.Arg572Ter variant protein resulted in a defective MRN complex and exhibited enhanced radio sensitivity in colony survival assays (Pitts et al. 2001; Delia et al. 2004). Based on the evidence, the p.Arg572Ter variant is classified as likely pathogenic for ataxia-telangiectasia-like disorder. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 21, 2024	- -

Ataxia-telangiectasia-like disorder

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 11, 2023	Variant summary: MRE11A c.1714C>T (p.Arg572X) 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. The variant allele was found at a frequency of 6e-05 in 251278 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in MRE11A causing Ataxia Telangiectasia-Like Disorder (6e-05 vs 0.0013), allowing no conclusion about variant significance. c.1714C>T has been reported in the literature in individuals affected with Ataxia Telangiectasia-like Disorder (Delia_2004, Pitts_2001), along with individuals affected with pancreatic cancer (Hu_2018) and breast cancer (Lolas Hamameh_2017). These data indicate that the variant is likely to be associated with disease. In addition, functional studies utilizing samples from compound heterozygote patients found the nonsense change to cause NMD leading to lack of MRE11A protein expression and causing an increased radiosensitivity (Delia_2004). The following publications have been ascertained in the context of this evaluation (PMID: 28152038, 29922827, 28486781, 15269180, 11371508, 10612394). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 29, 2023	This sequence change creates a premature translational stop signal (p.Arg572*) 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 also known as p.R571X. This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia-like disorder (PMID: 11371508, 15269180). This variant is present in population databases (rs137852761, gnomAD 0.01%). ClinVar contains an entry for this variant (Variation ID: 8784). For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2021

- -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 28, 2021

The p.R572* pathogenic mutation (also known as c.1714C>T), located in coding exon 14 of the MRE11A gene, results from a C to T substitution at nucleotide position 1714. This changes the amino acid from an arginine to a stop codon within coding exon 14. This mutation was reported in two siblings with ataxia telangiectasia-like disorder (ATLD) and was found to result in nonsense-mediated decay (Pitts SA et al. Hum. Mol. Genet. 2001 May;10:1155-62). In addition, two Italian siblings with ATLD were found to be compound heterozygous for this mutation, and their clinical course is well documented (Delia D et al. Hum. Mol. Genet. 2004 Sep;13:2155-63; Palmeri S et al. Cerebellum. 2013 Aug;12:596-9). Of note, this alteration is also designated as R571X in published literature. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.63

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Uncertain

0.96

MutationTaster

Benign

1.0

A;A;A;A

Vest4

0.90

GERP RS

5.2

RBP_binding_hub_radar

1.0

RBP_regulation_power_radar

2.1

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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