11-94437206-G-A

Variant names:

• chr11-94437206-G-A
• rs137852759
• NM_005591.4:c.1897C>T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_005591.4(MRE11):​c.1897C>T​(p.Arg633*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000248 in 1,612,588 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. R633R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: MRE11 NM_005591.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 1.35

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]

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 11-94437206-G-A is Pathogenic according to our data. Variant chr11-94437206-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 8782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MRE11	NM_005591.4	c.1897C>T	p.Arg633*	stop_gained	Exon 17 of 20	ENST00000323929.8	NP_005582.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MRE11	ENST00000323929.8	c.1897C>T	p.Arg633*	stop_gained	Exon 17 of 20	1	NM_005591.4	ENSP00000325863.4
MRE11	ENST00000323977.7	c.1813C>T	p.Arg605*	stop_gained	Exon 16 of 19	1		ENSP00000326094.3
MRE11	ENST00000407439.7	c.1906C>T	p.Arg636*	stop_gained	Exon 17 of 20	2		ENSP00000385614.3
MRE11	ENST00000393241.8	c.1894C>T	p.Arg632*	stop_gained	Exon 17 of 20	5		ENSP00000376933.4

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 151982 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000623

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000279 AC: 7 AN: 251072 AF XY: 0.0000368

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.0000246 AC: 36 AN: 1460606 Hom.: 0 Cov.: 30 AF XY: 0.0000358 AC XY: 26 AN XY: 726614

African (AFR) AF: 0.00 AC: 0 AN: 33448

American (AMR) AF: 0.0000224 AC: 1 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26098

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39536

South Asian (SAS) AF: 0.000232 AC: 20 AN: 86068

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53336

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1111332

Other (OTH) AF: 0.00 AC: 0 AN: 60336

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 151982 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74228

African (AFR) AF: 0.0000242 AC: 1 AN: 41362

American (AMR) AF: 0.00 AC: 0 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5204

South Asian (SAS) AF: 0.000623 AC: 3 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10560

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67998

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.0000341 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.0000547

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ataxia-telangiectasia-like disorder 1 Pathogenic:3

Feb 06, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 03, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

-

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The stop-gained variant c.1897C>T p.Arg633Ter in the MRE11 gene has been reported in the homozygous state in individuals affected with Ataxia telangiectasia and breast cancer Taylor et al., 2015; Bartkova et al., 2008. This variant is reported with the allele frequency 0.002% in the gnomAD Exomes and novel not in any individuals in 1000 Genomes. It has been submitted to ClinVar as Pathogenic Multiple submissions. This variant is predicted to cause a loss of normal protein function through protein truncation. Loss of function variants has been previously reported to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Jun 30, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 22863007, 25525159, 23912341, 10612394, 30625039, 29922827, 32832836, 31742824) -

Hereditary cancer-predisposing syndrome Pathogenic:1

Dec 13, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R633* pathogenic mutation (also known as c.1897C>T), located in coding exon 16 of the MRE11A gene, results from a C to T substitution at nucleotide position 1897. This changes the amino acid from an arginine to a stop codon within coding exon 16. This alteration was first described in a homozygous state in first cousins with ataxia-telangiectasia-like disorder (ATLD). Both individuals had features of A-T and increased levels of radiosensitivity, but no detectable ATM mutations (Stewart GS et al. Cell 1999; 99:577-87). The MRE11A p.R633* mutation has also been described in the homozygous state in siblings with ataxia (Chaki et al. Cell. 2012; 150:533-548). In another study, this alteration was detected in one individual with a personal and family history of breast cancer (Bartkova et al. J Mol Oncol. 2008; 2(4):296-316). This variant was also identified in a cohort of 3,579 African males diagnosed with prostate cancer who underwent multi-gene panel testing (Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. -

Ataxia-telangiectasia-like disorder Pathogenic:1

Nov 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg633*) 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 (rs137852759, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia-like disorder, nephronophthisis-related ciliopathies and/or breast cancer (PMID: 8445618, 10612394, 19383352, 22863007). ClinVar contains an entry for this variant (Variation ID: 8782). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects MRE11 function (PMID: 10612394, 14690604, 25040471). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	37
DANN	Uncertain	0.99
Eigen	Uncertain	0.35
Eigen_PC	Benign	0.11
FATHMM_MKL	Benign	0.47	N
PhyloP100		1.4
Vest4		0.90
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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

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Other links and lift over

dbSNP: rs137852759; hg19: chr11-94170372;