Submissions for variant NM_005591.4(MRE11):c.1643T>C (p.Ile548Thr)

gnomAD frequency: 0.00016  dbSNP: rs373522639

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131733	SCV000186774	uncertain significance	Hereditary cancer-predisposing syndrome	2022-09-30	criteria provided, single submitter	clinical testing	The p.I548T variant (also known as c.1643T>C), located in coding exon 14 of the MRE11A gene, results from a T to C substitution at nucleotide position 1643. The isoleucine at codon 548 is replaced by threonine, an amino acid with similar properties. This amino acid position is not 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	RCV000627772	SCV000254854	likely benign	Ataxia-telangiectasia-like disorder	2022-10-18	criteria provided, single submitter	clinical testing
Athena Diagnostics Inc	RCV000518010	SCV000614121	uncertain significance	not provided	2022-02-24	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001113939	SCV001271755	uncertain significance	Ataxia-telangiectasia-like disorder 1	2018-01-13	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.
Baylor Genetics	RCV001113939	SCV001481460	uncertain significance	Ataxia-telangiectasia-like disorder 1	2020-05-13	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Sema4, Sema4	RCV000131733	SCV002538398	uncertain significance	Hereditary cancer-predisposing syndrome	2021-05-17	criteria provided, single submitter	curation
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV001113939	SCV003920214	uncertain significance	Ataxia-telangiectasia-like disorder 1	2021-03-30	criteria provided, single submitter	clinical testing	MRE11 NM_005591.3 exon 15 p.Ile548Thr (c.1643T>C): This variant has not been reported in the literature but is present in 0.01% (24/128966) of European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/11-94180525-A-G?dataset=gnomad_r2_1). This variant is present in ClinVar (Variation ID:142542). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003323411	SCV004028945	likely benign	not specified	2023-07-21	criteria provided, single submitter	clinical testing	Variant summary: MRE11 c.1643T>C (p.Ile548Thr) 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 8e-05 in 251232 control chromosomes. The observed variant frequency is approximately 1.3 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.1643T>C has been reported in the literature as a VUS in settings of multigene panel testing in at least one individual with a personal and/or family history of cancer reportedly tested negative on routine BRCA analysis (e.g., Nunziato_2022). However, this report does 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 publication have been ascertained in the context of this evaluation (PMID: 36035419). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Six submitters classifieid it as a variant of uncertain significance, while one submitter classified it as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.