11-94471593-G-C

Variant names:

• chr11-94471593-G-C
• rs587782742
• NM_005591.4:c.826C>G

Variant summary

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

The NM_005591.4(MRE11):​c.826C>G​(p.Pro276Ala) variant causes a missense change involving the alteration of a 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, single submitter U:1
• Conservation: PhyloP100: 9.77

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 rank	MANE	Protein	UniProt
MRE11	NM_005591.4	c.826C>G	p.Pro276Ala	missense_variant	Exon 8 of 20	ENST00000323929.8	NP_005582.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MRE11	ENST00000323929.8	c.826C>G	p.Pro276Ala	missense_variant	Exon 8 of 20	1	NM_005591.4	ENSP00000325863.4
MRE11	ENST00000323977.7	c.826C>G	p.Pro276Ala	missense_variant	Exon 8 of 19	1		ENSP00000326094.3
MRE11	ENST00000407439.7	c.835C>G	p.Pro279Ala	missense_variant	Exon 8 of 20	2		ENSP00000385614.3
MRE11	ENST00000393241.8	c.826C>G	p.Pro276Ala	missense_variant	Exon 8 of 20	5		ENSP00000376933.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

May 24, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.P276A variant (also known as c.826C>G), located in coding exon 7 of the MRE11A gene, results from a C to G substitution at nucleotide position 826. The proline at codon 276 is replaced by alanine, an amino acid with highly similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6498 samples (12996 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 120000 alleles tested) in our clinical cohort. This amino acid position is highly conserved in available vertebrate species. 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	Benign	0.080
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.33	T;.;.;.
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Benign	0.076	D
MetaRNN	Uncertain	0.56	D;D;D;D
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Uncertain	2.2	M;.;M;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.3	D;D;D;D
REVEL	Uncertain	0.49
Sift	Benign	0.042	D;D;D;D
Sift4G	Benign	0.15	T;T;T;T
Polyphen		0.65	P;.;B;.
Vest4		0.64
MutPred		0.56		.;Gain of catalytic residue at P279 (P = 0.0388);.;.;
MVP		0.78
MPC		0.084
ClinPred		0.97	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.21
gMVP		0.48

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

Publications

LitVar

Other links and lift over

dbSNP: rs587782742; hg19: chr11-94204759;