NM_005591.4:c.1741G>A

Variant names:

• chr11-94447261-C-T
• rs864622095
• NM_005591.4:c.1741G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005591.4(MRE11):​c.1741G>A​(p.Gly581Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. G581G) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: MRE11 NM_005591.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.14
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MRE11	NM_005591.4	MANE Select	c.1741G>A	p.Gly581Arg	missense	Exon 15 of 20	NP_005582.1
	MRE11	NM_001440460.1		c.1741G>A	p.Gly581Arg	missense	Exon 15 of 21	NP_001427389.1
	MRE11	NM_001440461.1		c.1741G>A	p.Gly581Arg	missense	Exon 15 of 21	NP_001427390.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MRE11	ENST00000323929.8	TSL:1 MANE Select	c.1741G>A	p.Gly581Arg	missense	Exon 15 of 20	ENSP00000325863.4
	MRE11	ENST00000323977.7	TSL:1	c.1741G>A	p.Gly581Arg	missense	Exon 15 of 19	ENSP00000326094.3
	MRE11	ENST00000407439.7	TSL:2	c.1750G>A	p.Gly584Arg	missense	Exon 15 of 20	ENSP00000385614.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Ataxia-telangiectasia-like disorder (1)
-	1	-	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.070
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.51	D
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.049	D
MetaRNN	Uncertain	0.55	D
MetaSVM	Uncertain	0.15	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		5.1
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.43
Sift	Benign	0.093	T
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.60
MutPred		0.28		Gain of methylation at G584 (P = 0.0103)
MVP		0.86
MPC		0.43
ClinPred		0.88	D
GERP RS		6.1
Varity_R		0.14
gMVP		0.54
Mutation Taster		=52/48	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: rs864622095; hg19: chr11-94180427;