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

gnomAD frequency: 0.00006  dbSNP: rs375261439

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212568	SCV000149815	uncertain significance	not provided	2024-09-12	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 36922933, 29641532, 26787654, 28569743, 25452441, 31159747, 31942411)
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: seen in unaffected individuals, 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000524516	SCV000288932	uncertain significance	Ataxia-telangiectasia-like disorder	2025-01-20	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). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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	2024-03-26	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV003224151	SCV005631435	uncertain significance	Ataxia-telangiectasia-like disorder 1	2024-02-23	criteria provided, single submitter	clinical testing