rs137852761

Variant names:

• chr11-94447288-G-A
• rs137852761
• NM_005591.4:c.1714C>T
• MRE11 p.Arg572*

Your query was ambiguous. Multiple possible variants found:

• chr11-94447288-G-A
• chr11-94447288-G-C

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1 PS3 PP5_Very_Strong

The NM_005591.4(MRE11):​c.1714C>T​(p.Arg572*) 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 (★★). ClinVar reports functional evidence for this variant: "SCV000915562: 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" and additional evidence is available in ClinVar. 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 NM_005591.4 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 6.45
• Publications: 13 publications found

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 Gene-Disease associations (from GenCC):

• ataxia-telangiectasia-like disorder 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet, Ambry Genetics
• breast cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics
• familial ovarian cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• hereditary breast carcinoma

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• prostate cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 20 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000915562: 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).; SCV001362361: "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)." PMID: 28152038, 29922827, 28486781, 15269180, 11371508, 10612394
• PP5: Variant 11-94447288-G-A is Pathogenic according to our data. Variant chr11-94447288-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 8784.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005591.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MRE11	NM_005591.4	MANE Select	c.1714C>T	p.Arg572*	stop_gained	Exon 15 of 20	NP_005582.1	P49959-1
	MRE11	NM_001440460.1		c.1714C>T	p.Arg572*	stop_gained	Exon 15 of 21	NP_001427389.1
	MRE11	NM_001440461.1		c.1714C>T	p.Arg572*	stop_gained	Exon 15 of 21	NP_001427390.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MRE11	ENST00000323929.8	TSL:1 MANE Select	c.1714C>T	p.Arg572*	stop_gained	Exon 15 of 20	ENSP00000325863.4	P49959-1
	MRE11	ENST00000323977.7	TSL:1	c.1714C>T	p.Arg572*	stop_gained	Exon 15 of 19	ENSP00000326094.3	P49959-2
	MRE11	ENST00000936196.1		c.1714C>T	p.Arg572*	stop_gained	Exon 15 of 21	ENSP00000606255.1

Frequencies

GnomAD3 genomes AF: 0.0000659 AC: 10 AN: 151776 Hom.: 0 Cov.: 31

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

GnomAD2 exomes AF: 0.0000597 AC: 15 AN: 251278 AF XY: 0.0000663

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 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.: 0 Cov.: 31 AF XY: 0.000100 AC XY: 73 AN XY: 727196

African (AFR) AF: 0.0000299 AC: 1 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53358

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000123 AC: 137 AN: 1111984

Other (OTH) AF: 0.0000331 AC: 2 AN: 60384

GnomAD4 genome AF: 0.0000659 AC: 10 AN: 151776 Hom.: 0 Cov.: 31 AF XY: 0.0000540 AC XY: 4 AN XY: 74084

African (AFR) AF: 0.0000485 AC: 2 AN: 41274

American (AMR) AF: 0.00 AC: 0 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4790

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10524

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 67994

Other (OTH) AF: 0.00 AC: 0 AN: 2078

Alfa AF: 0.000161 Hom.: 0

Bravo AF: 0.0000416

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Ataxia-telangiectasia-like disorder 1 (4)
2	-	-	Ataxia-telangiectasia-like disorder (2)
1	-	-	Hereditary cancer-predisposing syndrome (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	40
DANN	Uncertain	1.0
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.96	D
PhyloP100		6.5
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.1
Mutation Taster		=0/200	disease causing (ClinVar)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs137852761;

hg19: chr11-94180454;

COSMIC: COSV60576548;