11-94420160-T-C

Variant names:

• chr11-94420160-T-C
• rs1805362
• NM_005591.4:c.2092A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005591.4(MRE11):​c.2092A>G​(p.Met698Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000993 in 1,582,312 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M698L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0055 (14 hom., cov: 33)
  • Exomes 𝑓: 0.00051 (11 hom.)
• Consequence: MRE11 NM_005591.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 2.02
• Publications: 9 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0042666793).
• BP6: Variant 11-94420160-T-C is Benign according to our data. Variant chr11-94420160-T-C is described in ClinVar as Benign. ClinVar VariationId is 129622.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00549 (836/152340) while in subpopulation AFR AF = 0.0192 (799/41578). AF 95% confidence interval is 0.0181. There are 14 homozygotes in GnomAd4. There are 368 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 14 AD,AR 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.2092A>G	p.Met698Val	missense	Exon 20 of 20	NP_005582.1	P49959-1
	MRE11	NM_001440460.1		c.2143A>G	p.Met715Val	missense	Exon 21 of 21	NP_001427389.1
	MRE11	NM_001440461.1		c.2143A>G	p.Met715Val	missense	Exon 21 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.2092A>G	p.Met698Val	missense	Exon 20 of 20	ENSP00000325863.4	P49959-1
	MRE11	ENST00000323977.7	TSL:1	c.2008A>G	p.Met670Val	missense	Exon 19 of 19	ENSP00000326094.3	P49959-2
	MRE11	ENST00000936196.1		c.2143A>G	p.Met715Val	missense	Exon 21 of 21	ENSP00000606255.1

Frequencies

GnomAD3 genomes AF: 0.00545 AC: 829 AN: 152222 Hom.: 13 Cov.: 33

Gnomad AFR AF: 0.0191

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00144 AC: 353 AN: 244464 AF XY: 0.00100

Gnomad AFR exome AF: 0.0190

Gnomad AMR exome AF: 0.000955

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000541

Gnomad OTH exome AF: 0.000825

GnomAD4 exome AF: 0.000514 AC: 735 AN: 1429972 Hom.: 11 Cov.: 28 AF XY: 0.000439 AC XY: 313 AN XY: 713102

African (AFR) AF: 0.0181 AC: 594 AN: 32838

American (AMR) AF: 0.000786 AC: 35 AN: 44542

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25860

East Asian (EAS) AF: 0.00 AC: 0 AN: 39320

South Asian (SAS) AF: 0.000117 AC: 10 AN: 85650

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47324

Middle Eastern (MID) AF: 0.000176 AC: 1 AN: 5694

European-Non Finnish (NFE) AF: 0.00000734 AC: 8 AN: 1089408

Other (OTH) AF: 0.00147 AC: 87 AN: 59336

GnomAD4 genome AF: 0.00549 AC: 836 AN: 152340 Hom.: 14 Cov.: 33 AF XY: 0.00494 AC XY: 368 AN XY: 74504

African (AFR) AF: 0.0192 AC: 799 AN: 41578

American (AMR) AF: 0.00144 AC: 22 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68020

Other (OTH) AF: 0.00378 AC: 8 AN: 2114

Alfa AF: 0.00198 Hom.: 6

Bravo AF: 0.00628

ESP6500AA AF: 0.0164 AC: 72

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00154 AC: 187

Asia WGS AF: 0.00376 AC: 13 AN: 3474

EpiCase AF: 0.0000546

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	4	Ataxia-telangiectasia-like disorder 1 (4)
-	-	2	not provided (2)
-	-	1	Ataxia-telangiectasia-like disorder (1)
-	-	1	Hereditary breast ovarian cancer syndrome (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	15
DANN	Benign	0.89
DEOGEN2	Benign	0.081	T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.18
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.62	T
MetaRNN	Benign	0.0043	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.9	L
PhyloP100		2.0
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.43	N
REVEL	Benign	0.13
Sift	Uncertain	0.021	D
Sift4G	Benign	0.66	T
Polyphen		0.011	B
Vest4		0.39
MVP		0.57
MPC		0.087
ClinPred		0.014	T
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.26
gMVP		0.12
Mutation Taster		=100/0	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: rs1805362; hg19: chr11-94153326;