rs372000848

chr11-94470575-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PP3_Strong BS2

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
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7
• Conservation: PhyloP100: 2.73

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 0 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.971
• BS2: High AC in GnomAd at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MRE11	NM_005591.4	c.913C>T	p.Arg305Trp	missense_variant	9/20	ENST00000323929.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MRE11	ENST00000323929.8	c.913C>T	p.Arg305Trp	missense_variant	9/20	1	NM_005591.4	P3
MRE11	ENST00000323977.7	c.913C>T	p.Arg305Trp	missense_variant	9/19	1
MRE11	ENST00000407439.7	c.922C>T	p.Arg308Trp	missense_variant	9/20	2
MRE11	ENST00000393241.8	c.913C>T	p.Arg305Trp	missense_variant	9/20	5		A1

Frequencies

GnomAD3 genomes AF: 0.0000724 AC: 11 AN: 152006 Hom.: 0 Cov.: 32

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

GnomAD3 exomes AF: 0.0000518 AC: 13 AN: 250984 Hom.: 0 AF XY: 0.0000516 AC XY: 7 AN XY: 135644

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 SAS 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: 70 AN: 1461028 Hom.: 0 Cov.: 31 AF XY: 0.0000495 AC XY: 36 AN XY: 726818

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000448

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.0000558

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000724 AC: 11 AN: 152006 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74258

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000975 Hom.: 0

Bravo AF: 0.0000416

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000494 AC: 6

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ataxia-telangiectasia-like disorder 1 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jan 08, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Apr 11, 2023	- -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 08, 2020	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) -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 17, 2018	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 Baker’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. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jul 31, 2023

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 31, 2023

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 08, 2022

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 and/or ovarian cancer (PMID: 14684699, 33956305). ClinVar contains an entry for this variant (Variation ID: 127989). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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	D
BayesDel_noAF	Pathogenic	0.49
Cadd	Uncertain	24
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.69	D;.;.;.
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.93	D;D;D;D
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Pathogenic	3.5	H;.;H;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.61	T
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	D
GERP RS		0.92
Varity_R		0.98
gMVP		0.88

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: rs372000848; hg19: chr11-94203741;