rs147383852

chr11-94471584-C-Gchr11-94471584-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_005591.4(MRE11):c.835G>C(p.Ala279Pro) 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 pathogenic 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. A279G) has been classified 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:3
• Conservation: PhyloP100: 3.30

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.871

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MRE11	NM_005591.4	c.835G>C	p.Ala279Pro	missense_variant	8/20	ENST00000323929.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MRE11	ENST00000323929.8	c.835G>C	p.Ala279Pro	missense_variant	8/20	1	NM_005591.4	P3
MRE11	ENST00000323977.7	c.835G>C	p.Ala279Pro	missense_variant	8/19	1
MRE11	ENST00000407439.7	c.844G>C	p.Ala282Pro	missense_variant	8/20	2
MRE11	ENST00000393241.8	c.835G>C	p.Ala279Pro	missense_variant	8/20	5		A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ataxia-telangiectasia-like disorder 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital

Jan 24, 2021

- -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 09, 2022

The p.A279P variant (also known as c.835G>C), located in coding exon 7 of the MRE11A gene, results from a G to C substitution at nucleotide position 835. The alanine at codon 279 is replaced by proline, 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 6499 samples (12998 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.002% (greater than 175000 alleles tested) in our clinical cohort. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be possibly damaging and deleterious by PolyPhen and SIFT in silico analyses, respectively. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Ataxia-telangiectasia-like disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 23, 2022

This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 279 of the MRE11 protein (p.Ala279Pro). This variant is not present in population databases (gnomAD no frequency). 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: 485811). 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: "Benign"; Align-GVGD: "Class C0"). 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	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T;.;.;.
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.87	D;D;D;D
MetaSVM	Uncertain	0.49	D
MutationAssessor	Pathogenic	3.1	M;.;M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-3.6	D;D;D;D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0020	D;D;D;D
Sift4G	Uncertain	0.0090	D;D;D;D
Polyphen		0.98	D;.;D;.
Vest4		0.76
MutPred		0.66		.;Gain of disorder (P = 0.0284);.;.;
MVP		0.79
MPC		0.23
ClinPred		0.99	D
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.93
gMVP		0.83

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: rs147383852; hg19: chr11-94204750; COSMIC: COSV60578501; COSMIC: COSV60578501;