11-94456280-C-G

Position:

• chr11-94456280-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005591.4(MRE11):​c.1559G>C​(p.Arg520Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MRE11 NM_005591.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.816

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MRE11	NM_005591.4	c.1559G>C	p.Arg520Pro	missense_variant	14/20	ENST00000323929.8	NP_005582.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MRE11	ENST00000323929.8	c.1559G>C	p.Arg520Pro	missense_variant	14/20	1	NM_005591.4	ENSP00000325863	P3
MRE11	ENST00000323977.7	c.1559G>C	p.Arg520Pro	missense_variant	14/19	1		ENSP00000326094
MRE11	ENST00000407439.7	c.1568G>C	p.Arg523Pro	missense_variant	14/20	2		ENSP00000385614
MRE11	ENST00000393241.8	c.1559G>C	p.Arg520Pro	missense_variant	14/20	5		ENSP00000376933	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

Nov 16, 2018

- -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 12, 2021

The p.R520P variant (also known as c.1559G>C), located in coding exon 13 of the MRE11A gene, results from a G to C substitution at nucleotide position 1559. The arginine at codon 520 is replaced by proline, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.13
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T;.;.;.
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.94	D;D;D;D
M_CAP	Benign	0.081	D
MetaRNN	Uncertain	0.53	D;D;D;D
MetaSVM	Benign	-0.36	T
MutationAssessor	Uncertain	2.5	M;.;M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.9	N;N;N;N
REVEL	Uncertain	0.33
Sift	Uncertain	0.018	D;D;D;D
Sift4G	Uncertain	0.055	T;T;T;T
Polyphen		0.74	P;.;P;.
Vest4		0.63
MutPred		0.25		.;Loss of helix (P = 0.0237);.;.;
MVP		0.78
MPC		0.37
ClinPred		0.86	D
GERP RS		5.8
Varity_R		0.60
gMVP		0.37

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

Publications

LitVar

Other links and lift over

dbSNP: rs753148077; hg19: chr11-94189446; COSMIC: COSV60580408;