MRE11 p.Asp517Glu

Variant names:

• chr11-94456288-A-T
• NM_005591.4:c.1551T>A
• MRE11 p.Asp517Glu

Your query was ambiguous. Multiple possible variants found:

• chr11-94456288-A-T
• chr11-94456288-A-C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005591.4(MRE11):​c.1551T>A​(p.Asp517Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D517A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MRE11 NM_005591.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.338
• 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: 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04928595).

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.1551T>A	p.Asp517Glu	missense	Exon 14 of 20	NP_005582.1	P49959-1
	MRE11	NM_001440460.1		c.1551T>A	p.Asp517Glu	missense	Exon 14 of 21	NP_001427389.1
	MRE11	NM_001440461.1		c.1551T>A	p.Asp517Glu	missense	Exon 14 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.1551T>A	p.Asp517Glu	missense	Exon 14 of 20	ENSP00000325863.4	P49959-1
	MRE11	ENST00000323977.7	TSL:1	c.1551T>A	p.Asp517Glu	missense	Exon 14 of 19	ENSP00000326094.3	P49959-2
	MRE11	ENST00000936196.1		c.1551T>A	p.Asp517Glu	missense	Exon 14 of 21	ENSP00000606255.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	14
DANN	Benign	0.91
DEOGEN2	Benign	0.060	T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.049	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.1	L
PhyloP100		0.34
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.15	N
REVEL	Benign	0.13
Sift	Benign	0.61	T
Sift4G	Benign	0.66	T
Varity_R		0.025
gMVP		0.067
Mutation Taster		=85/15	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr11-94189454; COSMIC: COSV108838177;