11-94429939-G-C

Variant names:

• chr11-94429939-G-C
• rs587782166
• NM_005591.4:c.2042C>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005591.4(MRE11):​c.2042C>G​(p.Ser681Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,558 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MRE11 NM_005591.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.19

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23529485).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MRE11	NM_005591.4	c.2042C>G	p.Ser681Trp	missense_variant	Exon 19 of 20	ENST00000323929.8	NP_005582.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MRE11	ENST00000323929.8	c.2042C>G	p.Ser681Trp	missense_variant	Exon 19 of 20	1	NM_005591.4	ENSP00000325863.4
MRE11	ENST00000323977.7	c.1958C>G	p.Ser653Trp	missense_variant	Exon 18 of 19	1		ENSP00000326094.3
MRE11	ENST00000407439.7	c.2051C>G	p.Ser684Trp	missense_variant	Exon 19 of 20	2		ENSP00000385614.3
MRE11	ENST00000393241.8	c.2039C>G	p.Ser680Trp	missense_variant	Exon 19 of 20	5		ENSP00000376933.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251384 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135862

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461558 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727090

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Jan 18, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.S681W variant (also known as c.2042C>G), located in coding exon 18 of the MRE11A gene, results from a C to G substitution at nucleotide position 2042. The serine at codon 681 is replaced by tryptophan, an amino acid with highly dissimilar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Ataxia-telangiectasia-like disorder Uncertain:1

Jul 17, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with tryptophan, which is neutral and slightly polar, at codon 681 of the MRE11 protein (p.Ser681Trp). This variant is present in population databases (no rsID available, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with MRE11-related conditions. ClinVar contains an entry for this variant (Variation ID: 481751). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.24	T;.;.;.
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.70	T;T;T;T
M_CAP	Benign	0.052	D
MetaRNN	Benign	0.24	T;T;T;T
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	0.69	N;.;.;.
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.7	N;N;N;N
REVEL	Benign	0.21
Sift	Uncertain	0.0030	D;D;D;D
Sift4G	Uncertain	0.030	D;D;D;D
Polyphen		0.85	P;.;P;.
Vest4		0.28
MutPred		0.17		.;Loss of phosphorylation at S684 (P = 0.0097);.;.;
MVP		0.72
MPC		0.30
ClinPred		0.58	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.048
gMVP		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs587782166; hg19: chr11-94163105;