11-94445959-T-C

Variant names:

• chr11-94445959-T-C
• rs1014666
• NM_005591.4:c.1784-66A>G

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.1784-66A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.464 in 1,106,224 control chromosomes in the GnomAD database, including 123,224 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.48 (17884 hom., cov: 33)
  • Exomes 𝑓: 0.46 (105340 hom.)
• Consequence: MRE11 NM_005591.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.676
• 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Orphanet
• 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=-0.81).
• BP6: Variant 11-94445959-T-C is Benign according to our data. Variant chr11-94445959-T-C is described in ClinVar as Benign. ClinVar VariationId is 1264255.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.587 is higher than 0.05.

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.1784-66A>G		intron	N/A	NP_005582.1	P49959-1
	MRE11	NM_001440460.1		c.1784-66A>G		intron	N/A	NP_001427389.1
	MRE11	NM_001440461.1		c.1784-66A>G		intron	N/A	NP_001427390.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MRE11	ENST00000323929.8	TSL:1 MANE Select	c.1784-66A>G		intron	N/A	ENSP00000325863.4	P49959-1
	MRE11	ENST00000323977.7	TSL:1	c.1783+1260A>G		intron	N/A	ENSP00000326094.3	P49959-2
	MRE11	ENST00000936196.1		c.1784-66A>G		intron	N/A	ENSP00000606255.1

Frequencies

GnomAD3 genomes AF: 0.482 AC: 73191 AN: 151932 Hom.: 17864 Cov.: 33

Gnomad AFR AF: 0.526

Gnomad AMI AF: 0.225

Gnomad AMR AF: 0.527

Gnomad ASJ AF: 0.456

Gnomad EAS AF: 0.492

Gnomad SAS AF: 0.604

Gnomad FIN AF: 0.466

Gnomad MID AF: 0.599

Gnomad NFE AF: 0.442

Gnomad OTH AF: 0.497

GnomAD4 exome AF: 0.462 AC: 440372 AN: 954174 Hom.: 105340 AF XY: 0.468 AC XY: 232080 AN XY: 495914

African (AFR) AF: 0.534 AC: 12493 AN: 23384

American (AMR) AF: 0.548 AC: 23349 AN: 42578

Ashkenazi Jewish (ASJ) AF: 0.478 AC: 10841 AN: 22700

East Asian (EAS) AF: 0.532 AC: 19915 AN: 37446

South Asian (SAS) AF: 0.615 AC: 45988 AN: 74772

European-Finnish (FIN) AF: 0.460 AC: 24124 AN: 52470

Middle Eastern (MID) AF: 0.562 AC: 2669 AN: 4750

European-Non Finnish (NFE) AF: 0.430 AC: 280795 AN: 652722

Other (OTH) AF: 0.466 AC: 20198 AN: 43352

GnomAD4 genome AF: 0.482 AC: 73256 AN: 152050 Hom.: 17884 Cov.: 33 AF XY: 0.487 AC XY: 36225 AN XY: 74322

African (AFR) AF: 0.526 AC: 21817 AN: 41470

American (AMR) AF: 0.527 AC: 8043 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.456 AC: 1578 AN: 3462

East Asian (EAS) AF: 0.491 AC: 2539 AN: 5168

South Asian (SAS) AF: 0.605 AC: 2918 AN: 4822

European-Finnish (FIN) AF: 0.466 AC: 4925 AN: 10560

Middle Eastern (MID) AF: 0.599 AC: 175 AN: 292

European-Non Finnish (NFE) AF: 0.442 AC: 30018 AN: 67978

Other (OTH) AF: 0.491 AC: 1038 AN: 2114

Alfa AF: 0.449 Hom.: 2589

Bravo AF: 0.483

Asia WGS AF: 0.529 AC: 1840 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.6
DANN	Benign	0.67
PhyloP100		-0.68
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs1014666; hg19: chr11-94179125; COSMIC: COSV60574018;