Submissions for variant NM_005591.4(MRE11):c.1727G>A (p.Arg576Gln)

gnomAD frequency: 0.00038  dbSNP: rs139461096

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000656868	SCV000149818	uncertain significance	not provided	2018-09-12	criteria provided, single submitter	clinical testing	MRE11A has only only recently been described in association with cancer predisposition and the risks are not well understood. This variant is denoted MRE11A c.1727G>A at the cDNA level, p.Arg576Gln (R576Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGA>CAA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MRE11A Arg576Gln was observed with allele frequencies of 0.05% (4/8596) and 0.02% (1/4402) in European and African Americans in the NHLBI Exome Sequencing Project respectively, which is not frequent enough to be considered a polymorphism. This variant is a semi-conservative substitution in which a positive polar amino acid is replaced with a neutral polar one, altering a position that is moderately conserved throughout evolution and tolerates the Arg>Gln substitution. MRE11A Arg576Gln is located within the GAR (glycine-arginine-rich) motif in the DNA-binding region (Stracker 2011). Studies in mice and cell based models demonstrate the requirement for the MRE11A GAR motif in regulating the ATR activation during DNA damage signaling and the maintenance of genomic stability (Yu 2012). In silico analyses predict this variant to have a benign effect on protein structure and function. On a molecular level, the impact of this missense variant on protein structure and function is not known and thus we consider this to be a variant of uncertain significance. Furthermore, based on the currently available information, cancer risks associated with this variant, and the MRE11A gene, remain unclear.
Ambry Genetics	RCV000115909	SCV000172853	likely benign	Hereditary cancer-predisposing syndrome	2018-11-06	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
Invitae	RCV001079651	SCV000254857	likely benign	Ataxia-telangiectasia-like disorder	2024-02-01	criteria provided, single submitter	clinical testing
Athena Diagnostics Inc	RCV001193484	SCV000614122	likely benign	not specified	2020-09-09	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000626883	SCV000747586	uncertain significance	Dystonic disorder; Depression; Parkinsonian disorder; Dementia	2017-01-01	criteria provided, single submitter	clinical testing
GeneKor MSA	RCV000115909	SCV000822029	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193484	SCV001362360	benign	not specified	2022-09-19	criteria provided, single submitter	clinical testing	Variant summary: MRE11 c.1727G>A (p.Arg576Gln) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00037 in 251374 control chromosomes, predominantly at a frequency of 0.00064 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 10 fold of the estimated maximal expected allele frequency for a pathogenic variant in MRE11 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (6.3e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.1727G>A has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome.A recent case-control study showed that this variant is not associated with breast cancer (Dorling_2021). Co-occurrence with a pathogenic variant has been reported (BRCA1 c.5359_5363delinsAGTGA, p.Cys1787_Gly1788delinsSerAsp), providing supporting evidence for a benign role. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign n=4, VUS n=3). Based on the evidence outlined above, the variant was classified as benign.
Sema4, Sema4	RCV000115909	SCV002538402	likely benign	Hereditary cancer-predisposing syndrome	2020-10-27	criteria provided, single submitter	curation
Revvity Omics, Revvity	RCV003133134	SCV003808915	uncertain significance	Ataxia-telangiectasia-like disorder 1	2019-12-07	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000656868	SCV004220917	likely benign	not provided	2022-04-13	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003952557	SCV004772928	uncertain significance	MRE11-related condition	2024-01-25	criteria provided, single submitter	clinical testing	The MRE11 c.1727G>A variant is predicted to result in the amino acid substitution p.Arg576Gln. This variant has been reported in multigene testing of BRCA1 and BRCA2 negative patients, although no further evidence was provided to determine its pathogenicity (Yadav et al. 2017. PubMed ID: 27878467). This variant has also been reported in individuals with breast cancer (Table S5 - Tsaousis et al. 2019. PubMed ID: 31159747; Table S15 - Caminsky et al. 2016. PubMed ID: 26898890). In ClinVar, it is reported as benign, likely benign, and uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/127974/). This variant is reported in 0.22% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-94180441-C-T), which is higher than expected for a fully penetrant ataxia-telangiectasia-like disorder 1 pathogenic variant. Although we suspect this variant is benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000656868	SCV001553687	uncertain significance	not provided		no assertion criteria provided	clinical testing	The MRE11 p.Arg576Gln variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs139461096) and ClinVar (reported likely benign and uncertain significance (5)). The c.1727G>A variant was identified in control databases in 96 of 282768 chromosomes at a frequency of 0.00034 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 23 of 10368 chromosomes (freq: 0.002218), Other in 7 of 7222 chromosomes (freq: 0.000969), Latino in 23 of 35436 chromosomes (freq: 0.000649), European (non-Finnish) in 35 of 129138 chromosomes (freq: 0.000271), South Asian in 6 of 30614 chromosomes (freq: 0.000196) and African in 2 of 24968 chromosomes (freq: 0.00008); it was not observed in the East Asian or European (Finnish) populations. The p.Arg576 residue is not conserved in mammals and five of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, and MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.