rs137868143

Variant names:

• chr11-94471597-A-G
• rs137868143
• NM_005591.4:c.822T>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_001440460.1(MRE11):​c.822T>C​(p.Leu274Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00138 in 1,612,580 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0015 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (5 hom.)
• Consequence: MRE11 NM_001440460.1 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:13
• Conservation: PhyloP100: 0.709
• Publications: 2 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 11-94471597-A-G is Benign according to our data. Variant chr11-94471597-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 182549.
• BP7: Synonymous conserved (PhyloP=0.709 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 5 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001440460.1. 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.822T>C	p.Leu274Leu	synonymous	Exon 8 of 20	NP_005582.1
	MRE11	NM_001440460.1		c.822T>C	p.Leu274Leu	synonymous	Exon 8 of 21	NP_001427389.1
	MRE11	NM_001440461.1		c.822T>C	p.Leu274Leu	synonymous	Exon 8 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.822T>C	p.Leu274Leu	synonymous	Exon 8 of 20	ENSP00000325863.4
	MRE11	ENST00000323977.7	TSL:1	c.822T>C	p.Leu274Leu	synonymous	Exon 8 of 19	ENSP00000326094.3
	MRE11	ENST00000936196.1		c.822T>C	p.Leu274Leu	synonymous	Exon 8 of 21	ENSP00000606255.1

Frequencies

GnomAD3 genomes AF: 0.00145 AC: 221 AN: 152046 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000722

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00253

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00140 AC: 352 AN: 250874 AF XY: 0.00147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.000895

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00305

Gnomad NFE exome AF: 0.00235

Gnomad OTH exome AF: 0.000981

GnomAD4 exome AF: 0.00137 AC: 2001 AN: 1460416 Hom.: 5 Cov.: 31 AF XY: 0.00145 AC XY: 1054 AN XY: 726512

African (AFR) AF: 0.0000299 AC: 1 AN: 33414

American (AMR) AF: 0.000201 AC: 9 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.000691 AC: 18 AN: 26068

East Asian (EAS) AF: 0.00 AC: 0 AN: 39616

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86214

European-Finnish (FIN) AF: 0.00309 AC: 165 AN: 53328

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 0.00159 AC: 1764 AN: 1111024

Other (OTH) AF: 0.000680 AC: 41 AN: 60324

GnomAD4 genome AF: 0.00145 AC: 221 AN: 152164 Hom.: 1 Cov.: 32 AF XY: 0.00149 AC XY: 111 AN XY: 74414

African (AFR) AF: 0.0000962 AC: 4 AN: 41568

American (AMR) AF: 0.000721 AC: 11 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00282 AC: 30 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00253 AC: 172 AN: 67930

Other (OTH) AF: 0.00142 AC: 3 AN: 2110

Alfa AF: 0.00196 Hom.: 0

Bravo AF: 0.000952

EpiCase AF: 0.00186

EpiControl AF: 0.00154

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	1	2	Ataxia-telangiectasia-like disorder 1 (3)
-	-	3	not provided (3)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	1	Ataxia-telangiectasia-like disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	6.6
DANN	Benign	0.83
PhyloP100		0.71
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=96/4	polymorphism

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: rs137868143; hg19: chr11-94204763;