Submissions for variant NM_005591.4(MRE11):c.1811G>A (p.Arg604His)

dbSNP: rs148637964

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212572	SCV000149820	uncertain significance	not provided	2014-02-11	criteria provided, single submitter	clinical testing	MRE11A has been only recently described in association with cancer predisposition and the risks are not well understood. This variant is denoted MRE11A c.1811G>A at the cDNA level, p.Arg604His (R604H) at the protein level, and results in the change of an Arginine to a Histidine (CGT>CAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MRE11A Arg604His was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. This variant is a conservative substitution of one positive polar amino acid for another, altering a position that is moderately conserved throughout evolution and is not located in a known functional domain. 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	RCV000115911	SCV000186113	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-21	criteria provided, single submitter	clinical testing	The p.R604H variant (also known as c.1811G>A), located in coding exon 15 of the MRE11A gene, results from a G to A substitution at nucleotide position 1811. The arginine at codon 604 is replaced by histidine, an amino acid with highly similar properties. In one study, this variant was reported in 2/1313 early-onset breast cancer cases and 1/1123 population controls (Damiola F et al. Breast Cancer Res. 2014 Jun;16:R58). In another study, this variant was observed in 1/287 patients with hereditary breast and/or ovarian cancer; this patient was diagnosed with breast cancers at age 52 and 54 and had a family history of breast and ovarian cancers in second- and third-degree relatives (Caminsky NG et al. Hum. Mutat. 2016 Jul;37:640-52). This alteration was also reported in a study of 1297 cases of early-onset breast cancer and 1121 controls (Young EL et al. J. Med. Genet. 2016 Jun;53:366-76). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000791355	SCV000254859	uncertain significance	Ataxia-telangiectasia-like disorder	2022-10-16	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 604 of the MRE11 protein (p.Arg604His). This variant is present in population databases (rs148637964, gnomAD 0.04%). This missense change has been observed in individual(s) with breast cancer (PMID: 24894818, 32658311). ClinVar contains an entry for this variant (Variation ID: 127976). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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.
Counsyl	RCV000411847	SCV000489096	uncertain significance	Ataxia-telangiectasia-like disorder 1	2016-08-17	criteria provided, single submitter	clinical testing
Athena Diagnostics Inc	RCV000212572	SCV000842793	uncertain significance	not provided	2021-12-27	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000411847	SCV000896211	uncertain significance	Ataxia-telangiectasia-like disorder 1	2018-10-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000411847	SCV001270278	uncertain significance	Ataxia-telangiectasia-like disorder 1	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001778710	SCV002014927	uncertain significance	not specified	2023-08-08	criteria provided, single submitter	clinical testing	Variant summary: MRE11 c.1811G>A (p.Arg604His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00022 in 250994 control chromosomes (gnomAD). The observed variant frequency is approximately 3-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 benign. c.1811G>A has been reported in the literature in individuals affected with breast cancer or other disorders, as well as unaffected controls (e.g. Damiola_2014, Kienzler_2016, Young_2016, Caminsky_2016, Akcay_2021, Dorling_2021). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 26787654, 26898890, 24894818, 32658311, 26680607, 33471991). Eight 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 VUS-possibly benign.
Sema4, Sema4	RCV000115911	SCV002538410	uncertain significance	Hereditary cancer-predisposing syndrome	2021-05-03	criteria provided, single submitter	curation
CeGaT Center for Human Genetics Tuebingen	RCV000212572	SCV002585342	uncertain significance	not provided	2022-08-01	criteria provided, single submitter	clinical testing	MRE11: PM2, BP4
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV000411847	SCV004176498	uncertain significance	Ataxia-telangiectasia-like disorder 1	2023-03-01	criteria provided, single submitter	clinical testing	The missense variant c.1811G>A (p.Arg604His) in MRE11 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is reported with the allele frequency 0.02% in the gnomAD Exomes and novel in 1000 Genomes. The amino acid Arg at position 604 is changed to a His changing protein sequence and it might alter its composition and physico-chemical properties. The residue is conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212572	SCV004220919	likely benign	not provided	2023-03-21	criteria provided, single submitter	clinical testing