rs535801

Positions:

• chr11-94478882-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005591.4(MRE11):​c.403-6G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.31 in 1,611,268 control chromosomes in the GnomAD database, including 79,257 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (6977 hom., cov: 33)
  • Exomes 𝑓: 0.31 (72280 hom.)
• Consequence: MRE11 NM_005591.4 splice_region, intron
• Scores: Splicing: ADA: 0.0001265
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -2.42

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 11-94478882-C-T is Benign according to our data. Variant chr11-94478882-C-T is described in ClinVar as [Benign]. Clinvar id is 129623.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-94478882-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.377 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MRE11	NM_005591.4	c.403-6G>A		splice_region_variant, intron_variant		ENST00000323929.8	NP_005582.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MRE11	ENST00000323929.8	c.403-6G>A		splice_region_variant, intron_variant		1	NM_005591.4	ENSP00000325863.4

Frequencies

GnomAD3 genomes AF: 0.295 AC: 44888 AN: 151914 Hom.: 6979 Cov.: 33

Gnomad AFR AF: 0.206

Gnomad AMI AF: 0.211

Gnomad AMR AF: 0.384

Gnomad ASJ AF: 0.316

Gnomad EAS AF: 0.391

Gnomad SAS AF: 0.356

Gnomad FIN AF: 0.368

Gnomad MID AF: 0.396

Gnomad NFE AF: 0.306

Gnomad OTH AF: 0.323

GnomAD3 exomes AF: 0.334 AC: 83483 AN: 249894 Hom.: 14391 AF XY: 0.333 AC XY: 45014 AN XY: 135078

Gnomad AFR exome AF: 0.200

Gnomad AMR exome AF: 0.426

Gnomad ASJ exome AF: 0.335

Gnomad EAS exome AF: 0.398

Gnomad SAS exome AF: 0.348

Gnomad FIN exome AF: 0.360

Gnomad NFE exome AF: 0.306

Gnomad OTH exome AF: 0.332

GnomAD4 exome AF: 0.311 AC: 454419 AN: 1459236 Hom.: 72280 Cov.: 34 AF XY: 0.313 AC XY: 227213 AN XY: 726006

Gnomad4 AFR exome AF: 0.209

Gnomad4 AMR exome AF: 0.422

Gnomad4 ASJ exome AF: 0.335

Gnomad4 EAS exome AF: 0.414

Gnomad4 SAS exome AF: 0.352

Gnomad4 FIN exome AF: 0.351

Gnomad4 NFE exome AF: 0.301

Gnomad4 OTH exome AF: 0.310

GnomAD4 genome AF: 0.295 AC: 44891 AN: 152032 Hom.: 6977 Cov.: 33 AF XY: 0.301 AC XY: 22370 AN XY: 74320

Gnomad4 AFR AF: 0.206

Gnomad4 AMR AF: 0.385

Gnomad4 ASJ AF: 0.316

Gnomad4 EAS AF: 0.391

Gnomad4 SAS AF: 0.355

Gnomad4 FIN AF: 0.368

Gnomad4 NFE AF: 0.306

Gnomad4 OTH AF: 0.319

Alfa AF: 0.307 Hom.: 5972

Bravo AF: 0.294

Asia WGS AF: 0.338 AC: 1176 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 06, 2016	Variant summary: The c.403-6G>A variant affects a non-conserved intronic nucleotide. MutationTaster tool predicts benign outcome for this variant. 5/5 splice-tools in Alamut predict that this variant does not affect normal splicing. This variant is found in 39196/120518 control chromosomes (including 6588 homozygotes) from ExAC at a frequency of 0.3252294, which is about 5204 times greater than the maximal expected frequency of a pathogenic allele (0.0000625), suggesting this variant is a common benign polymorphism. One clinical laboratory has classified this variant as likely benign. Taken together, this variant has been classified as Benign. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Ataxia-telangiectasia-like disorder 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

Ataxia-telangiectasia-like disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Hereditary breast ovarian cancer syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

National Health Laboratory Service, Universitas Academic Hospital and University of the Free State

Apr 19, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.26
DANN	Benign	0.40
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00013
dbscSNV1_RF	Benign	0.0020
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

LitVar

Other links and lift over

dbSNP: rs535801; hg19: chr11-94212048; COSMIC: COSV60575621; COSMIC: COSV60575621;