Submissions for variant NM_005591.4(MRE11):c.1462C>T (p.Arg488Cys)

gnomAD frequency: 0.00006  dbSNP: rs375261439

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212568	SCV000149815	uncertain significance	not provided	2014-03-04	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.1462C>T at the cDNA level, p.Arg488Cys (R488C) at the protein level, and results in the change of an Arginine to a Cysteine (CGT>TGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MRE11A Arg488Cys was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. This variant is a non-conservative substitution in which a positive polar amino acid is replaced with a neutral polar one, altering a position that is highly conserved throughout evolution and is not located in a known functional domain. Multiple in silico algorithms predict that this variant may be damaging to 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	RCV000115906	SCV000186536	likely benign	Hereditary cancer-predisposing syndrome	2018-08-23	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	RCV000524516	SCV000288932	uncertain significance	Ataxia-telangiectasia-like disorder	2022-10-17	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 488 of the MRE11 protein (p.Arg488Cys). This variant is present in population databases (rs375261439, gnomAD 0.02%). This missense change has been observed in individual(s) with breast cancer and in individuals undergoing genetic testing for hereditary cancer predisposition (PMID: 25452441, 31159747). ClinVar contains an entry for this variant (Variation ID: 127972). 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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; 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.
GeneKor MSA	RCV000115906	SCV000822028	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003224151	SCV003920216	uncertain significance	Ataxia-telangiectasia-like disorder 1	2021-12-22	criteria provided, single submitter	clinical testing	MRE11 NM_005591.4 exon 13 p.Arg488Cys (c.1462C>T): This variant has been observed in individuals in at least 10 individuals undergoing genetic testing for hereditary cancer predisposition (Couch 2015 PMID:25452441; Tsaousis 2019 PMID:31159747). It is present in 0.02% (26/129120) European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/11-94192612-G-A?dataset=gnomad_r2_1). This variant is present in ClinVar with classifications ranging from likely benign to VUS (Variation ID: 127972). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Baylor Genetics	RCV003224151	SCV004193827	uncertain significance	Ataxia-telangiectasia-like disorder 1	2023-07-28	criteria provided, single submitter	clinical testing