rs372000848

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PP3_Strong

The NM_005591.4(MRE11):c.913C>T(p.Arg305Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000502 in 1,613,034 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R305Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000048 ( 0 hom. )

Consequence

MRE11
NM_005591.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:7

Conservation

PhyloP100: 2.73

Publications

15 publications found

Variant links:

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

MRE11 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.971

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MRE11	NM_005591.4 link	c.913C>T	p.Arg305Trp	missense_variant	Exon 9 of 20	ENST00000323929.8	NP_005582.1	P49959-1A0A024R395

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MRE11	ENST00000323929.8 link	c.913C>T	p.Arg305Trp	missense_variant	Exon 9 of 20	1	NM_005591.4	ENSP00000325863.4	P49959-1
MRE11	ENST00000323977.7 link	c.913C>T	p.Arg305Trp	missense_variant	Exon 9 of 19	1		ENSP00000326094.3	P49959-2
MRE11	ENST00000407439.7 link	c.922C>T	p.Arg308Trp	missense_variant	Exon 9 of 20	2		ENSP00000385614.3	P49959-3
MRE11	ENST00000393241.8 link	c.913C>T	p.Arg305Trp	missense_variant	Exon 9 of 20	5		ENSP00000376933.4	F8W7U8

Frequencies

GnomAD3 genomes

AF:

0.0000724

AC:

AN:

152006

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000518

AC:

AN:

250984

AF XY:

0.0000516

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000925

Gnomad NFE exome

AF:

0.0000793

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000479

AC:

AN:

1461028

Hom.:

Cov.:

AF XY:

0.0000495

AC XY:

AN XY:

726818

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33446

American (AMR)

AF:

0.0000448

AC:

AN:

44682

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26110

East Asian (EAS)

AF:

0.00

AC:

AN:

39650

South Asian (SAS)

AF:

0.00

AC:

AN:

86228

European-Finnish (FIN)

AF:

0.0000374

AC:

AN:

53406

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0000558

AC:

AN:

1111392

Other (OTH)

AF:

0.0000331

AC:

AN:

60350

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000724

AC:

AN:

152006

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74258

show subpopulations

African (AFR)

AF:

0.0000242

AC:

AN:

41406

American (AMR)

AF:

0.00

AC:

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.0000943

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

67948

Other (OTH)

AF:

0.00

AC:

AN:

2082

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000716

Hom.:

Bravo

AF:

0.0000416

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Ataxia-telangiectasia-like disorder 1

Uncertain:2

Jan 08, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 11, 2023

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:2

Jan 17, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Arg305Trp variant has been reported in a heterozygous form in one individual with ovarian cancer (Heikkinen 2003). This variant (rs372000848) is listed in the Genome Aggregation Database (gnomAD) with allele frequency of 0.009 percent in non-Finnish European populations (identified on 11 out of 126,314) and has been reported to the ClinVar database (Variation ID: 127989). Arginine at codon 305 is highly conserved considering 13 species, up to Bakerâ€™s yeast (Alamut v2.10), and computational analyses support a deleterious impact on the protein structure and function (PolyPhen2: possibly damaging, SIFT: damaging, and Mutation Taster: disease causing). Altogether, the clinical significance of p.Arg305Trp variant cannot be determined with certainty. -

Jan 08, 2020

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 15855896, 14684699, 23747889, 22078559, 18606567, 21715099) -

not specified

Uncertain:1

Jul 31, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: MRE11 c.913C>T (p.Arg305Trp) results in a non-conservative amino acid change located in the Mre11, DNA-binding domain (IPR007281) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.7e-05 in 282364 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in MRE11 causing Hereditary Breast And Ovarian Cancer Syndrome (5.7e-05 vs 6.3e-05), allowing no conclusion about variant significance. c.913C>T has been reported in the literature in individuals affected with ovarian cancer, prostate cancer or cerebellar ataxia (Heikkinen_2003, Rantapero_2020, da Graa_2021). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function and it showed hR305W was sensitive to DNA damage reagents (MMS/HU) (Harris_2021). The following publications have been ascertained in the context of this evaluation (PMID: 33510186, 34075539, 14684699, 24093751, 22078559, 32183364, 33956305). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Hereditary cancer-predisposing syndrome

Uncertain:1

Oct 31, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R305W variant (also known as c.913C>T), located in coding exon 8 of the MRE11A gene, results from a C to T substitution at nucleotide position 913. The arginine at codon 305 is replaced by tryptophan, an amino acid with dissimilar properties. This variant has been reported in the compound heterozygous state with a second alteration in MRE11A (c.1442C>A, p.Thr481Lys) in a patient with ataxia at age 7; however, the phase of these two alterations was not confirmed (da Graça FF et al. Cerebellum, 2022 Feb;21:49-54). This alteration has also been reported in one ovarian cancer patient from a cohort of 151 families with signs of hereditary susceptibility to breast and/or ovarian cancer (Heikkinen K et al. J. Med. Genet. 2003 Dec;40:e131). Further, structural analysis of this amino acid position has shown that the p.R305W alteration is predicted to perturb interactions between the guanidium group of Arg305 and the carbonyl oxygen of Lys360 (Park YB et al. Structure. 2011 Nov;19:1591-602). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious 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

Dec 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 305 of the MRE11 protein (p.Arg305Trp). This variant is present in population databases (rs372000848, gnomAD 0.01%). This missense change has been observed in individual(s) with cerebellar ataxia, ovarian cancer, and/or prostate cancer (PMID: 14684699, 32183364, 33956305). ClinVar contains an entry for this variant (Variation ID: 127989). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects MRE11 function (PMID: 34075539). 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

0.37

BayesDel_noAF

Pathogenic

0.49

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.69

D;.;.;.

Eigen

Uncertain

0.38

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.93

D;D;D;D

M_CAP

Pathogenic

0.35

MetaRNN

Pathogenic

0.97

D;D;D;D

MetaSVM

Pathogenic

0.87

MutationAssessor

Pathogenic

3.5

H;.;H;.

PhyloP100

2.7

PrimateAI

Uncertain

0.61

PROVEAN

Pathogenic

-7.9

D;D;D;D

REVEL

Pathogenic

0.85

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Uncertain

0.033

D;D;D;D

Polyphen

0.96

D;.;D;.

Vest4

0.98

MVP

0.85

MPC

0.45

ClinPred

0.75

GERP RS

0.92

Varity_R

0.98

gMVP

0.88

Mutation Taster

=1/99

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over