Submissions for variant NM_005591.4(MRE11):c.1475C>A (p.Ala492Asp)

gnomAD frequency: 0.00399  dbSNP: rs61749249

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000114897	SCV000149816	likely benign	not provided	2020-12-14	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 28051113, 26898890, 26483394, 30666157)
Ambry Genetics	RCV000115907	SCV000172746	benign	Hereditary cancer-predisposing syndrome	2014-08-07	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Genetic Services Laboratory, University of Chicago	RCV000193395	SCV000248073	likely benign	not specified	2021-09-22	criteria provided, single submitter	clinical testing	DNA sequence analysis of the MRE11A gene demonstrated a sequence change, c.1475C>A, in exon 13 that results in an amino acid change, p.Ala492Asp. This sequence change does not appear to have been previously described in patients with MRE11A-related disorders and has been described in the gnomAD database with a reatively high frequency of 0.56% in the European sub-population (dbSNP rs61749249). The p.Ala492Asp change affects a moderately conserved amino acid residue located in a domain of the MRE11A protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Ala492Asp substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Ala492Asp change remains unknown at this time.
Invitae	RCV001079570	SCV000253443	benign	Ataxia-telangiectasia-like disorder	2024-01-31	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000193395	SCV000341540	likely benign	not specified	2016-04-25	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000524517	SCV000604243	uncertain significance	Ataxia-telangiectasia-like disorder 1	2023-10-14	criteria provided, single submitter	clinical testing	The MRE11 c.1475C>A; p.Ala492Asp variant (rs61749249) is reported in the literature in individuals with hereditary breast and ovarian cancer syndrome, colon cancer, or pancreatic cancer (Caminsky 2016, Castellanos 2017, Hu 2016, Taghizadeh 2020). However, this variant is also found in the non-Finnish European population with an allele frequency of 0.56% (720/129116 alleles, including 3 homozygotes) in the Genome Aggregation Database. This variant is reported in the ClinVar database (Variation ID: 127031). The alanine at codon 492 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.234). Based on available information, the clinical significance of this variant is uncertain at this time. References: Caminsky NG et al. Prioritizing Variants in Complete Hereditary Breast and Ovarian Cancer Genes in Patients Lacking Known BRCA Mutations. Hum Mutat. 2016 Jul;37(7):640-52. PMID: 26898890 Castellanos E et al. A comprehensive custom panel design for routine hereditary cancer testing: preserving control, improving diagnostics and revealing a complex variation landscape. Sci Rep. 2017 Jan 4;7:39348. PMID: 28051113 Hu C et al. Prevalence of Pathogenic Mutations in Cancer Predisposition Genes among Pancreatic Cancer Patients. Cancer Epidemiol Biomarkers Prev. 2016 Jan;25(1):207-11. PMID: 26483394 Taghizadeh H et al. Applied precision medicine in metastatic pancreatic ductal adenocarcinoma. Ther Adv Med Oncol. 2020 Jul 10;12:1758835920938611. PMID: 32699558;
Counsyl	RCV000524517	SCV000785308	likely benign	Ataxia-telangiectasia-like disorder 1	2017-07-05	criteria provided, single submitter	clinical testing
Athena Diagnostics Inc	RCV000193395	SCV000842789	benign	not specified	2020-01-06	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000114897	SCV001148387	likely benign	not provided	2024-01-01	criteria provided, single submitter	clinical testing	MRE11: BS2
Illumina Laboratory Services, Illumina	RCV000524517	SCV001271758	benign	Ataxia-telangiectasia-like disorder 1	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.
Baylor Genetics	RCV000524517	SCV001483058	uncertain significance	Ataxia-telangiectasia-like disorder 1	2018-11-30	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000114897	SCV002010542	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV002225316	SCV002504809	likely benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115907	SCV002538394	benign	Hereditary cancer-predisposing syndrome	2020-10-19	criteria provided, single submitter	curation
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000193395	SCV002774025	benign	not specified	2020-01-06	criteria provided, single submitter	clinical testing
Harris Lab, University of Minnesota	RCV000114897	SCV000148792	not provided	not provided		no assertion provided	not provided
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000114897	SCV001799829	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000114897	SCV001929018	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000114897	SCV001971956	likely benign	not provided		no assertion criteria provided	clinical testing