11-94459433-G-T

Variant names:

• chr11-94459433-G-T
• rs61749249
• NM_005591.4:c.1475C>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_005591.4(MRE11):​c.1475C>A​(p.Ala492Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00604 in 1,613,870 control chromosomes in the GnomAD database, including 47 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A492V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0039 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0063 (46 hom.)
• Consequence: MRE11 NM_005591.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:16 O:1
• Conservation: PhyloP100: 4.87
• Publications: 27 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0070512593).
• BP6: Variant 11-94459433-G-T is Benign according to our data. Variant chr11-94459433-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 127031.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.00626 (9149/1461648) while in subpopulation NFE AF = 0.0076 (8452/1111842). AF 95% confidence interval is 0.00747. There are 46 homozygotes in GnomAdExome4. There are 4322 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 46 AR,AD gene

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.1475C>A	p.Ala492Asp	missense	Exon 13 of 20	NP_005582.1	P49959-1
	MRE11	NM_001440460.1		c.1475C>A	p.Ala492Asp	missense	Exon 13 of 21	NP_001427389.1
	MRE11	NM_001440461.1		c.1475C>A	p.Ala492Asp	missense	Exon 13 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.1475C>A	p.Ala492Asp	missense	Exon 13 of 20	ENSP00000325863.4	P49959-1
	MRE11	ENST00000323977.7	TSL:1	c.1475C>A	p.Ala492Asp	missense	Exon 13 of 19	ENSP00000326094.3	P49959-2
	MRE11	ENST00000936196.1		c.1475C>A	p.Ala492Asp	missense	Exon 13 of 21	ENSP00000606255.1

Frequencies

GnomAD3 genomes AF: 0.00392 AC: 596 AN: 152104 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00121

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00537

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00666

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00345 AC: 867 AN: 251386 AF XY: 0.00316

Gnomad AFR exome AF: 0.000738

Gnomad AMR exome AF: 0.00489

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000462

Gnomad NFE exome AF: 0.00568

Gnomad OTH exome AF: 0.00473

GnomAD4 exome AF: 0.00626 AC: 9149 AN: 1461648 Hom.: 46 Cov.: 31 AF XY: 0.00594 AC XY: 4322 AN XY: 727140

African (AFR) AF: 0.00105 AC: 35 AN: 33476

American (AMR) AF: 0.00512 AC: 229 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86252

European-Finnish (FIN) AF: 0.000524 AC: 28 AN: 53408

Middle Eastern (MID) AF: 0.00122 AC: 7 AN: 5754

European-Non Finnish (NFE) AF: 0.00760 AC: 8452 AN: 1111842

Other (OTH) AF: 0.00644 AC: 389 AN: 60390

GnomAD4 genome AF: 0.00392 AC: 596 AN: 152222 Hom.: 1 Cov.: 32 AF XY: 0.00349 AC XY: 260 AN XY: 74430

African (AFR) AF: 0.00120 AC: 50 AN: 41532

American (AMR) AF: 0.00536 AC: 82 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10608

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

European-Non Finnish (NFE) AF: 0.00666 AC: 453 AN: 68006

Other (OTH) AF: 0.00284 AC: 6 AN: 2112

Alfa AF: 0.00521 Hom.: 13

Bravo AF: 0.00423

TwinsUK AF: 0.00836 AC: 31

ALSPAC AF: 0.00830 AC: 32

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00628 AC: 54

ExAC AF: 0.00338 AC: 411

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00649

EpiControl AF: 0.00599

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	5	not provided (7)
-	2	2	Ataxia-telangiectasia-like disorder 1 (4)
-	-	4	not specified (4)
-	-	3	Hereditary cancer-predisposing syndrome (3)
-	-	1	Ataxia-telangiectasia-like disorder (1)
-	-	1	Hereditary breast ovarian cancer syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.055	D
MetaRNN	Benign	0.0071	T
MetaSVM	Benign	-0.42	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		4.9
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.23
Sift	Benign	0.12	T
Sift4G	Benign	0.25	T
Polyphen		0.95	P
Vest4		0.58
MVP		0.78
MPC		0.32
ClinPred		0.054	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.35
gMVP		0.41
Mutation Taster		=98/2	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: rs61749249; hg19: chr11-94192599; COSMIC: COSV104651895;