11-94478882-C-T

Variant names:

• chr11-94478882-C-T
• rs535801
• NM_005591.4:c.403-6G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 54 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: Benign. The variant received -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 VariationId is 129623.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
MRE11	NM_005591.4	c.403-6G>A		splice_region_variant, intron_variant	Intron 5 of 19	ENST00000323929.8	NP_005582.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MRE11	ENST00000323929.8	c.403-6G>A		splice_region_variant, intron_variant	Intron 5 of 19	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

GnomAD2 exomes AF: 0.334 AC: 83483 AN: 249894 AF XY: 0.333

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 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

African (AFR) AF: 0.209 AC: 6998 AN: 33424

American (AMR) AF: 0.422 AC: 18859 AN: 44668

Ashkenazi Jewish (ASJ) AF: 0.335 AC: 8739 AN: 26104

East Asian (EAS) AF: 0.414 AC: 16415 AN: 39606

South Asian (SAS) AF: 0.352 AC: 30370 AN: 86200

European-Finnish (FIN) AF: 0.351 AC: 18632 AN: 53018

Middle Eastern (MID) AF: 0.348 AC: 2003 AN: 5758

European-Non Finnish (NFE) AF: 0.301 AC: 333729 AN: 1110172

Other (OTH) AF: 0.310 AC: 18674 AN: 60286

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

African (AFR) AF: 0.206 AC: 8539 AN: 41494

American (AMR) AF: 0.385 AC: 5875 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.316 AC: 1096 AN: 3470

East Asian (EAS) AF: 0.391 AC: 2017 AN: 5158

South Asian (SAS) AF: 0.355 AC: 1715 AN: 4828

European-Finnish (FIN) AF: 0.368 AC: 3880 AN: 10544

Middle Eastern (MID) AF: 0.398 AC: 117 AN: 294

European-Non Finnish (NFE) AF: 0.306 AC: 20787 AN: 67944

Other (OTH) AF: 0.319 AC: 673 AN: 2110

Alfa AF: 0.307 Hom.: 10810

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

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 06, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Ataxia-telangiectasia-like disorder 1 Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Ataxia-telangiectasia-like disorder Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome Benign:1

Apr 19, 2022

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.26
DANN	Benign	0.40
PhyloP100		-2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

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