Inheritance

Autosomal recessive

Prevalence

1/100,000 (rare)

source: orphanet

Rapid or full curation?

ClinGen / GenCC / BabySeq / HGMD

No curations in ClinGen, supporting in GenCC (orphanet), none in Babyseq supplement.

HGMD variants reviewed below.

Clinical Validity Scoring Notes and points

CASE LEVEL

• c.350A>G p.N117S - 1/113084 European gnomAD, 0.000008843, only allele in gnomAD. PMID: 10612394 Two patients ATLD3 and ATLD4, are siblings with clinical features of ataxia telangiectasia (progressive cerebellar degeneration, but no ocular telangiectasias). Cells from these individuals had chromosomal instability and increased sensitivity to ionizing radiation.  Father is het, mother appears wt at this position. Unclear if mom has a deletion present, or UPD. Fig 4 - Jun kinase activity in patient cells is similar to AT cells compared to normal. Position is not conserved, plus consanguinity present). 0 POINTS

• c.168G>T p.L56F (1 allele all gnomAD, 1/34524 Latino chrome, 0.00005, REVEL = 0.895). PMID: 25133958  Compound het with c.497C>T Pro166Leu (absent gnomAD, REVEL=0.946) in patient ATX70, a 37yo F with ataxia, early onset <20y, extrapyramidal features and oculomotor apraxia and a brother who is also affected. Identified via exome sequencing.  0.5pts x 2 = 1 POINT

• PMID: 31033087 - 3 Patients, all variants confirmed in trans per main text. P1 compound het c.424G>A  p.D142N (GNOMAD 1/113278 European non-Finnish, 0.000008, but REVEL is only 0.182) with c.544G>A Gly182Arg (1/15408 Eur non-Finnish 0.00006, last base of exon, predicted splice impact). Abnormal splicing resulting in RNA observed (3 products, r.315_544del/ p.(Phe106Ilefs*5)), r.315_659del/p.(Phe106_Arg220del) and a small amount had the missense). c.424G>A p.D142N variant was also reported in patient P2 with c.1726C>T p.Arg576* (6/113686 Eur non-Finnish 0.00005, NMD+). P3 was compound het for c.529_530delinsAT, p.(Ala177Met (absent gnomAD, no REVEL data, but highly conserved) and c.314+4_314+7del (1/113299 Eur non-Finnish 0.000008, predicted altered splicing). All variants confirmed in trans. They were sequenced for MRE11 after normal ATM sequencing. All three had progressive cerebellar ataxia. Reduced expression in all three patients on Western shown fig 3. Variant scoring: P1 - 1+1, P2 - 2.5, P3 - 1+1 = TOTAL 6.5 POINTS.

• c.630G>C p.W210C - absent gnomAD, REVEL 0.839. PMID: 15574463 - reported in 10 patients homozygous, with early onset, slowly progressive ataxia plus ocular apraxia. No tumor development or telangiectasias. The patients were Saudi Arabian. Identified via linkage, only one candidate region shared homozygosity in all 4 affected sibs from one family. Two known ataxia genes in the interval ATM and MRE11. 5 affected segregation, 6 unaffected across the two families in fig 1, 2 POINTS. Experimental data from patient fibroblasts showed high constitutive levels of Mre11 and Rad50 proteins, but low levels of Nbs1, exposure to radiation showed failure to form Mre11 foci and enhanced radiation sensitivity. Variant evidence 0.5 - 0.5 (consanguinity) + 0.5pts for functional = 0.5 POINTS

• c.727T>C p.W243R - Did not review

• c.908C>T p.T303I - did not review

• c.1714C>T p.R572* - 14/129026 European nonFinnish alleles, NMD+. PMID: 11371508: Per text on p3, a single base change C>T at nucleotide 1714 found in the DNA of patients ATLD3 and 4, who were previously reported with the N117S variant in PMID: 10612394, but the second variant in the mother wasn’t found in the prior study. 1 seg. Variant also reported in PMID: 15269180 in an additional two affected siblings with cerebellar degeneration, slowly progressing until puberty. Second variant 1422C>A,T481K. 1 seg. NMD+  variant reported twice 2 SEGS, max score 3 POINTS

• c.1897C>T p.R633* - Exon 17/20, NMD+. 6/30560 South Asian alleles in gnomAD, 0.0001963. PMID: 10612394 - describes two cousins, ATLD1 and ATLD2 who are both homozygous for the variant. The family is consanguineous. All parents confirmed het per caption of Fig 2. Fig 1 shows that there are reduced protein levels of MRE11 protein in patient cells. Fig 3A, survival of cells from ATLD2 was similar to classic A-T. Fig 4 - Jun kinase activity in patient cells is similar to AT cells compared to normal. NMD+ hom variant and rare phenotype with functional evidence 3 POINTS

16 POINTS GENETIC EVIDENCE AND REPLICATED OVER TIME

Clinical Validity Points Total

12

Clinical Validity Classification

Definitive

Molecular Mechanism

LOSS-OF-FUNCTION

See full details in clinical validity scoring. 3 NMD+ variants - p.R633* (exon 17), p.R572* (exon 15), and  p.Arg576* (exon 15)

Penetrance

(list source/PMID)

Complete

(no evidence of reduced penetrance described evidence used for clinical validity scoring)

Age of Onset

(list source/PMID)

Childhood

Severity

Severe/Moderate

Clinical Features

Early-onset, progressive ataxia with cerebellar degeneration, without evidence of telangiectasias or tumor development.

Gene SOPs & Notes

Curation Summary:

The MRE11 gene is associated with autosomal recessive ataxia, which is characterized by early-onset, progressive ataxia with cerebellar degeneration, without evidence of telangiectasias or tumor development. 

Case ID, Curator name, Date, Jira ticket link

Andrea Oza 06/14/2023, https://broadinstitute.atlassian.net/browse/CIT-127

Inheritance

Autosomal dominant

Prevalence

 126.9 per 100,000 women per year with breast carcinoma (Common)

Source: Cancer of the Breast (Female) - Cancer Stat Facts

Rapid or full curation?

ClinGen / GenCC / BabySeq / HGMD

ClinGen Hereditary Cancer GCEP 03/14/2023

Clinical Validity Scoring Notes and points

MRE11 (also known as MRE11A) is part of the MRN (MRE11-RAD50-NBN) complex and is involved in repairing double strand breaks in DNA. Bi-allelic mutations in MRE11 are associated with the recessive Ataxia-telangiectasia-like disorder 1. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we have split MRE11 into two separate curations - one for the recessive Ataxia-telangiectasia-like disorder 1 and the second for hereditary breast cancer (refute the association with breast cancer) described here. Evidence refuting this gene-disease relationship includes case-control data, while experimental data supports the role of MRE11 in DNA damage repair.

Summary of Case-Control Data: 0 POINTS

This gene-disease relationship has been studied in at least 4 case-control studies at the aggregate variant level and 1 case-control cohort at the single variant level. In 2021, two large case-control studies [CARRIERS (PMID: 33471974) and BCAC (PMID: 33471991); both with more than 32 thousand cases and controls] did not identify a significant association of aggregate loss of function (LOF) variants in MRE11 and breast cancer. Likewise, another large case-control study published in 2017 (Couch et al. PMID: 28418444) screened breast cancer cases from commercial laboratories and did not find significant association of pathogenic mutations in MRE11 with breast cancer. Two more case-control studies with smaller case and control sizes also showed no association of LOF or missense MRE11 variants with breast cancer (PMID: 29368209 and 29678143).

Summary of Experimental Data: 1 POINTS

While case control studies did not support the gene-disease association, there is experimental evidence showing the role of MRE11 in double-strand DNA break repair (0.5 point, PMID:9651580). Another study reported reduced MRE11 expression in breast cancer tissues (0.5 point, PMID:14511253).

Overall Summary:

In summary, given the lack of significant association in large breast cancer case-control studies to date, there is convincing evidence refuting the association between MRE11 and autosomal dominant hereditary breast cancer, which significantly outweighs the evidence supporting the association. This gene-disease pair was originally evaluated as disputed by the Breast/Ovarian Cancer GCEP on 10/25/2017. This re-curation was approved by the ClinGen Hereditary Diseases GCEP on 2/17/2023 (SOP Version 9).

Gene Clinical Validity Standard Operating Procedures (SOP) - SOP9

Source: ClinGen Hereditary Cancer GCEP 03/14/2023

Clinical Validity Points Total

n/a

Source:

Clinical Validity Classification

REFUTED

Source: ClinGen Hereditary Cancer GCEP 03/14/2023

Molecular Mechanism

n/a

Penetrance

(list source/PMID)

n/a

Source:

Age of Onset

(list source/PMID)

n/a

Severity

n/a

Clinical Features

n/a

Sources:

Gene SOPs & Notes

 LINK if SOP is a long document. Short notes if it is easy to digest. eg. Last known truncating variant

Curation Summary:

Curation Summary:

Case ID, Curator name, Date, Jira ticket link

Andrea Oza 06/14/2023, https://broadinstitute.atlassian.net/browse/CIT-127