rs374685908

Variant names:

• chr11-94420153-G-A
• rs374685908
• NM_005591.4:c.2099C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-94420153-G-A
• chr11-94420153-G-C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_005591.4(MRE11):​c.2099C>T​(p.Thr700Ile) 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. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T700S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MRE11 NM_005591.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.107
• Publications: 1 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: Orphanet, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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 -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.02508244).
• BP6: Variant 11-94420153-G-A is Benign according to our data. Variant chr11-94420153-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 820711.Status of the report is criteria_provided_single_submitter, 1 stars.

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.2099C>T	p.Thr700Ile	missense	Exon 20 of 20	NP_005582.1
	MRE11	NM_001440460.1		c.2150C>T	p.Thr717Ile	missense	Exon 21 of 21	NP_001427389.1
	MRE11	NM_001440461.1		c.2150C>T	p.Thr717Ile	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.2099C>T	p.Thr700Ile	missense	Exon 20 of 20	ENSP00000325863.4
	MRE11	ENST00000323977.7	TSL:1	c.2015C>T	p.Thr672Ile	missense	Exon 19 of 19	ENSP00000326094.3
	MRE11	ENST00000936196.1		c.2150C>T	p.Thr717Ile	missense	Exon 21 of 21	ENSP00000606255.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	5.6
DANN	Benign	0.79
DEOGEN2	Benign	0.091	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0039	N
LIST_S2	Benign	0.51	T
M_CAP	Benign	0.0080	T
MetaRNN	Benign	0.025	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.20	N
PhyloP100		-0.11
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.73	N
REVEL	Benign	0.18
Sift	Benign	0.25	T
Sift4G	Benign	0.42	T
Polyphen		0.0	B
Vest4		0.044
MutPred		0.098		Loss of solvent accessibility (P = 0.0674)
MVP		0.33
MPC		0.090
ClinPred		0.93	D
GERP RS		-5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.025
gMVP		0.11
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs374685908; hg19: chr11-94153319;