chr11-94464194-TA-T

Variant names:

• chr11-94464194-TA-T
• rs863224508
• NM_005591.4:c.1143delT

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_005591.4(MRE11):​c.1143delT​(p.Phe381LeufsTer9) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MRE11 NM_005591.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 2.56

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

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-94464194-TA-T is Pathogenic according to our data. Variant chr11-94464194-TA-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 216094.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.1143delT	p.Phe381LeufsTer9	frameshift_variant	Exon 11 of 20	ENST00000323929.8	NP_005582.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MRE11	ENST00000323929.8	c.1143delT	p.Phe381LeufsTer9	frameshift_variant	Exon 11 of 20	1	NM_005591.4	ENSP00000325863.4
MRE11	ENST00000323977.7	c.1143delT	p.Phe381LeufsTer9	frameshift_variant	Exon 11 of 19	1		ENSP00000326094.3
MRE11	ENST00000407439.7	c.1152delT	p.Phe384LeufsTer9	frameshift_variant	Exon 11 of 20	2		ENSP00000385614.3
MRE11	ENST00000393241.8	c.1143delT	p.Phe381LeufsTer9	frameshift_variant	Exon 11 of 20	5		ENSP00000376933.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:2

Mar 28, 2016

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1143delT pathogenic mutation, located in coding exon 10 of the MRE11A gene, results from a deletion of one nucleotide at nucleotide position 1143, causing a translational frameshift with a predicted alternate stop codon. 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. -

May 18, 2015

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 at codon 381 (p.Phe381Leufs*9). It is expected to result in an absent or disrupted protein product. While this particular variant has not been reported in the literature, truncating variants in MRE11A are known to be pathogenic PMID: 10612394, 11371508). For these reasons, this variant has been classified as Pathogenic. -

Ataxia-telangiectasia-like disorder 1 Pathogenic:1

Oct 17, 2023

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Ataxia-telangiectasia-like disorder Pathogenic:1

Jul 17, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 216094). This variant has not been reported in the literature in individuals affected with MRE11A-related conditions. This sequence change creates a premature translational stop signal (p.Phe381Leufs*9) in the MRE11A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MRE11A are known to be pathogenic (PMID: 23080121, 23912341). -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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

Other links and lift over

dbSNP: rs863224508; hg19: chr11-94197360;