11-94445885-C-T

Variant names:

• chr11-94445885-C-T
• rs587781951
• NM_005591.4:c.1792G>A

Variant summary

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

The NM_005591.4(MRE11):​c.1792G>A​(p.Gly598Ser) 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. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G598R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MRE11 NM_005591.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.630
• Publications: 2 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05489129).

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.1792G>A	p.Gly598Ser	missense	Exon 16 of 20	NP_005582.1	P49959-1
	MRE11	NM_001440460.1		c.1792G>A	p.Gly598Ser	missense	Exon 16 of 21	NP_001427389.1
	MRE11	NM_001440461.1		c.1792G>A	p.Gly598Ser	missense	Exon 16 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.1792G>A	p.Gly598Ser	missense	Exon 16 of 20	ENSP00000325863.4	P49959-1
	MRE11	ENST00000323977.7	TSL:1	c.1783+1334G>A		intron	N/A	ENSP00000326094.3	P49959-2
	MRE11	ENST00000936196.1		c.1792G>A	p.Gly598Ser	missense	Exon 16 of 21	ENSP00000606255.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

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	0.067
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	0.46
DANN	Benign	0.37
DEOGEN2	Benign	0.055	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.038	N
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.055	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		-0.63
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.11	N
REVEL	Benign	0.055
Sift	Benign	0.59	T
Sift4G	Benign	0.92	T
Polyphen		0.0	B
Vest4		0.082
MutPred		0.18		Gain of phosphorylation at G601 (P = 0.0124)
MVP		0.32
MPC		0.083
ClinPred		0.075	T
GERP RS		-0.38
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.1
Varity_R		0.028
gMVP		0.26
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs587781951; hg19: chr11-94179051;