11-94447288-G-C

Variant names:

• chr11-94447288-G-C
• rs137852761
• NM_005591.4:c.1714C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005591.4(MRE11):​c.1714C>G​(p.Arg572Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,788 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R572Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MRE11 NM_005591.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.45
• Publications: 0 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: Labcorp Genetics (formerly Invitae), G2P, Orphanet, Ambry Genetics
• 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: Uncertain_significance. The variant received 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.1714C>G	p.Arg572Gly	missense_variant	Exon 15 of 20	ENST00000323929.8	NP_005582.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MRE11	ENST00000323929.8	c.1714C>G	p.Arg572Gly	missense_variant	Exon 15 of 20	1	NM_005591.4	ENSP00000325863.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461788 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727196

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53358

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111984

Other (OTH) AF: 0.00 AC: 0 AN: 60384

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Mar 17, 2020

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R572G variant (also known as c.1714C>G), located in coding exon 14 of the MRE11A gene, results from a C to G substitution at nucleotide position 1714. The arginine at codon 572 is replaced by glycine, an amino acid with dissimilar properties. 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	0.21
BayesDel_addAF	Uncertain	0.095	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	23
DANN	Benign	0.96
DEOGEN2	Benign	0.40	T;.;.;.
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.73	T;T;T;T
M_CAP	Uncertain	0.094	D
MetaRNN	Uncertain	0.45	T;T;T;T
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Uncertain	2.6	M;.;M;.
PhyloP100		6.5
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-3.3	D;D;D;D
REVEL	Uncertain	0.46
Sift	Benign	0.32	T;T;T;T
Sift4G	Uncertain	0.0030	D;D;D;D
Polyphen		0.96	D;.;P;.
Vest4		0.47
MutPred		0.33		.;Loss of methylation at R575 (P = 0.002);.;.;
MVP		0.83
MPC		0.53
ClinPred		0.95	D
GERP RS		5.2
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.1
Varity_R		0.21
gMVP		0.66
Mutation Taster		=33/67	disease causing

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: rs137852761; hg19: chr11-94180454; COSMIC: COSV60580710;