11-94490953-G-T

Variant names:

• chr11-94490953-G-T
• rs746088302
• NM_005591.4:c.33C>A

Variant summary

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

The NM_005591.4(MRE11):​c.33C>A​(p.Asn11Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000761 in 1,313,648 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). 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. N11S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.6e-7 (0 hom.)
• Consequence: MRE11 NM_005591.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.21
• 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: 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MRE11	NM_005591.4	MANE Select	c.33C>A	p.Asn11Lys	missense	Exon 3 of 20	NP_005582.1	P49959-1
	MRE11	NM_001440460.1		c.33C>A	p.Asn11Lys	missense	Exon 3 of 21	NP_001427389.1
	MRE11	NM_001440461.1		c.33C>A	p.Asn11Lys	missense	Exon 3 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.33C>A	p.Asn11Lys	missense	Exon 3 of 20	ENSP00000325863.4	P49959-1
	MRE11	ENST00000323977.7	TSL:1	c.33C>A	p.Asn11Lys	missense	Exon 3 of 19	ENSP00000326094.3	P49959-2
	MRE11	ENST00000540013.5	TSL:1	c.33C>A	p.Asn11Lys	missense	Exon 3 of 8	ENSP00000440986.1	F5GXT0

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.61e-7 AC: 1 AN: 1313648 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 660988

African (AFR) AF: 0.00 AC: 0 AN: 30376

American (AMR) AF: 0.00 AC: 0 AN: 44358

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25192

East Asian (EAS) AF: 0.00 AC: 0 AN: 38886

South Asian (SAS) AF: 0.00 AC: 0 AN: 82966

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52164

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4966

European-Non Finnish (NFE) AF: 0.00000102 AC: 1 AN: 979390

Other (OTH) AF: 0.00 AC: 0 AN: 55350

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

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	0.35
BayesDel_addAF	Benign	-0.041	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T
Eigen	Benign	0.044
Eigen_PC	Benign	-0.030
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.45	T
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		2.2
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.43
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.99	D
Vest4		0.41
MutPred		0.52		Gain of ubiquitination at N14 (P = 0.0192)
MVP		0.69
MPC		0.25
ClinPred		0.98	D
GERP RS		0.88
Varity_R		0.69
gMVP		0.52
Mutation Taster		=52/47	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs746088302; hg19: chr11-94224119;