11-94470486-G-C

Variant names:

• chr11-94470486-G-C
• rs115244417
• NM_005591.4:c.1002C>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.1002C>G​(p.Ser334Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00247 in 1,612,802 control chromosomes in the GnomAD database, including 80 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. S334N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.013 (43 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (37 hom.)
• Consequence: MRE11 NM_005591.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 2.01
• Publications: 8 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=0.0035775304).
• BP6: Variant 11-94470486-G-C is Benign according to our data. Variant chr11-94470486-G-C is described in ClinVar as Benign. ClinVar VariationId is 140946.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 = 0.0129 (1955/152130) while in subpopulation AFR AF = 0.0443 (1839/41518). AF 95% confidence interval is 0.0426. There are 43 homozygotes in GnomAd4. There are 919 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 43 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.1002C>G	p.Ser334Arg	missense	Exon 9 of 20	NP_005582.1	P49959-1
	MRE11	NM_001440460.1		c.1002C>G	p.Ser334Arg	missense	Exon 9 of 21	NP_001427389.1
	MRE11	NM_001440461.1		c.1002C>G	p.Ser334Arg	missense	Exon 9 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.1002C>G	p.Ser334Arg	missense	Exon 9 of 20	ENSP00000325863.4	P49959-1
	MRE11	ENST00000323977.7	TSL:1	c.1002C>G	p.Ser334Arg	missense	Exon 9 of 19	ENSP00000326094.3	P49959-2
	MRE11	ENST00000936196.1		c.1002C>G	p.Ser334Arg	missense	Exon 9 of 21	ENSP00000606255.1

Frequencies

GnomAD3 genomes AF: 0.0128 AC: 1947 AN: 152012 Hom.: 43 Cov.: 32

Gnomad AFR AF: 0.0442

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00460

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.00911

GnomAD2 exomes AF: 0.00353 AC: 886 AN: 251082 AF XY: 0.00242

Gnomad AFR exome AF: 0.0470

Gnomad AMR exome AF: 0.00220

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000282

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00139 AC: 2036 AN: 1460672 Hom.: 37 Cov.: 31 AF XY: 0.00120 AC XY: 875 AN XY: 726656

African (AFR) AF: 0.0450 AC: 1504 AN: 33422

American (AMR) AF: 0.00257 AC: 115 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26094

East Asian (EAS) AF: 0.00 AC: 0 AN: 39642

South Asian (SAS) AF: 0.000128 AC: 11 AN: 86222

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00209 AC: 12 AN: 5740

European-Non Finnish (NFE) AF: 0.000183 AC: 203 AN: 1111144

Other (OTH) AF: 0.00317 AC: 191 AN: 60322

GnomAD4 genome AF: 0.0129 AC: 1955 AN: 152130 Hom.: 43 Cov.: 32 AF XY: 0.0124 AC XY: 919 AN XY: 74354

African (AFR) AF: 0.0443 AC: 1839 AN: 41518

American (AMR) AF: 0.00459 AC: 70 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000382 AC: 26 AN: 67984

Other (OTH) AF: 0.00901 AC: 19 AN: 2108

Alfa AF: 0.000696 Hom.: 2

Bravo AF: 0.0146

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0450 AC: 198

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00413 AC: 502

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Ataxia-telangiectasia-like disorder 1 (4)
-	-	4	not provided (4)
-	-	2	not specified (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	0.23
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	19
DANN	Benign	0.92
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.13
Eigen_PC	Benign	0.075
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.0036	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.14	N
PhyloP100		2.0
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.11
Sift	Benign	0.52	T
Sift4G	Benign	0.17	T
Polyphen		0.18	B
Vest4		0.30
MutPred		0.38		Gain of catalytic residue at S337 (P = 0.0638)
MVP		0.76
MPC		0.099
ClinPred		0.0079	T
GERP RS		4.6
Varity_R		0.24
gMVP		0.32
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs115244417; hg19: chr11-94203652; COSMIC: COSV104651900;