MRE11 (aka MRE11a) Gene Curation

Gene-disease assertions not curated here (add link or write note):

Disease	Ataxia
Inheritance	Autosomal recessive
Prevalence Possible sources Orphanet Medline Plus Genetics	1/100,000 (rare) source: orphanet
Rapid or full curation?	Rapid Full
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.(Phe106Ilefs5)), 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 Classifications (pts) Definitive (12pts) Strong (12pts) Moderate (7-11pts) Limited (0.1-6pts) No genetic evidence Refuted Disputed	Definitive
Molecular Mechanism Mechanisms Loss of function Gain of function Dominant negative Unknown Other	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 options Complete (100%) High (≥90%) Reduced (<90% and >10%) Low (≤10%) (list source/PMID)	Complete (no evidence of reduced penetrance described evidence used for clinical validity scoring)
Age of Onset options Congenital Pediatric Adolescent Adulthood Late adulthood (list source/PMID)	Childhood
Severity Options Embryonic lethal - presence of a pathogenic variant or variants is not compatible with life. The penetrance must be complete. Severe - presence of a pathogenic variant or variant(s) results in significantly reduced fitness. The penetrance must be complete or high. Moderate - significant morbidity or mortality due to clinical features, but fitness may not be reduced, or penetrance is reduced. Mild - Presence of a variant or variant(s) is not associated with reduced fitness, no significant morbidity or mortality, and/or penetrance is low. None - presence of a variant results in no phenotype. An example is recessive disorders in which no phenotype is reported in carriers.	Severe/Moderate
Clinical Features	Early-onset, progressive ataxia with cerebellar degeneration, without evidence of telangiectasias or tumor development.
Gene SOPs & Notes
Curation Summary: Examples - The @GENE@ is associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs). - Variable expression or severity: The severity and expressivity of the disorder is highly variable, even within families. - If multiple conditions associated with the gene: It has also been associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs). - Limited evidence gene: The PCNA gene has been reported in individuals with early onset autosomal recessive ataxia (PMID: 33426167, 24911150), however, evidence supporting this gene-dsiease relationship is limited	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, CIT-127 - Getting issue details... STATUS

Disease	hereditary breast carcinoma
Inheritance	Autosomal dominant
Prevalence Possible sources Orphanet Medline Plus Genetics	126.9 per 100,000 women per year with breast carcinoma (Common) Source: https://seer.cancer.gov/statfacts/html/breast.html
Rapid or full curation?	Rapid Full
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 Classifications (pts) Definitive (12pts) Strong (12pts) Moderate (7-11pts) Limited (0.1-6pts) No genetic evidence Refuted Disputed	REFUTED Source: ClinGen Hereditary Cancer GCEP 03/14/2023
Molecular Mechanism Mechanisms Loss of function Gain of function Dominant negative Unknown Other	n/a
Penetrance options Complete (100%) High (≥90%) Reduced (<90% and >10%) Low (≤10%) (list source/PMID)	n/a Source:
Age of Onset options Congenital Pediatric Adolescent Adulthood Late adulthood (list source/PMID)	n/a
Severity Options Embryonic lethal - presence of a pathogenic variant or variants is not compatible with life. The penetrance must be complete. Severe - presence of a pathogenic variant or variant(s) results in significantly reduced fitness. The penetrance must be complete or high. Moderate - significant morbidity or mortality due to clinical features, but fitness may not be reduced, or penetrance is reduced. Mild - Presence of a variant or variant(s) is not associated with reduced fitness, no significant morbidity or mortality, and/or penetrance is low. None - presence of a variant results in no phenotype. An example is recessive disorders in which no phenotype is reported in carriers.	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: Examples - The @GENE@ is associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs). - Variable expression or severity: The severity and expressivity of the disorder is highly variable, even within families. - If multiple conditions associated with the gene: It has also been associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs). - Limited evidence gene: The PCNA gene has been reported in individuals with early onset autosomal recessive ataxia (PMID: 33426167, 24911150), however, evidence supporting this gene-dsiease relationship is limited	Curation Summary: Examples The MRE11 gene has been reported in individuals with breast carcinoma; however, evidence supporting this gene-disease relationship has been reviewed in detail and is refuted by the ClinGen Hereditary Cancer Gene Curation Expert Panel based on a lack of association observed in case-control studies (PMID: 33471974, 33471991, 28418444, 29368209 and 29678143).
Case ID, Curator name, Date, Jira ticket link	Andrea Oza 06/14/2023, CIT-127 - Getting issue details... STATUS