rs776688385

Variant names:

• chr11-94447329-G-A
• rs776688385
• NM_005591.4:c.1673C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-94447329-G-A
• chr11-94447329-G-C

Variant summary

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

The NM_005591.4(MRE11):​c.1673C>T​(p.Ser558Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: MRE11 NM_005591.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.66

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.1673C>T	p.Ser558Phe	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.1673C>T	p.Ser558Phe	missense_variant	Exon 15 of 20	1	NM_005591.4	ENSP00000325863.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

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

Apr 25, 2018

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.S558F variant (also known as c.1673C>T), located in coding exon 14 of the MRE11A gene, results from a C to T substitution at nucleotide position 1673. The serine at codon 558 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This amino acid position is well 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Uncertain	0.036	T
BayesDel_noAF	Benign	-0.19
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T;.;.;.
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.88	D;D;D;D
M_CAP	Uncertain	0.092	D
MetaRNN	Uncertain	0.47	T;T;T;T
MetaSVM	Uncertain	0.017	D
MutationAssessor	Uncertain	2.5	M;.;M;.
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-2.5	D;D;N;N
REVEL	Uncertain	0.32
Sift	Benign	0.080	T;T;T;T
Sift4G	Uncertain	0.0090	D;D;D;D
Polyphen		1.0	D;.;D;.
Vest4		0.48
MutPred		0.18		.;Loss of phosphorylation at S561 (P = 0.0202);.;.;
MVP		0.87
MPC		0.47
ClinPred		0.93	D
GERP RS		5.7
Varity_R		0.16
gMVP		0.33

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: rs776688385; hg19: chr11-94180495; COSMIC: COSV60575751; COSMIC: COSV60575751;