Submissions for variant NM_005591.4(MRE11):c.120C>T (p.Leu40=)

gnomAD frequency: 0.00066  dbSNP: rs1805364

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212552	SCV000211161	benign	not specified	2013-11-06	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics	RCV000160575	SCV000213020	likely benign	Hereditary cancer-predisposing syndrome	2014-08-29	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	RCV001080131	SCV000253440	likely benign	Ataxia-telangiectasia-like disorder	2024-01-29	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000524512	SCV000744083	likely benign	Ataxia-telangiectasia-like disorder 1	2017-01-04	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000524512	SCV000745567	likely benign	Ataxia-telangiectasia-like disorder 1	2017-06-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000212552	SCV000917681	benign	not specified	2018-12-21	criteria provided, single submitter	clinical testing	Variant summary: The variant MRE11A c.120C>T alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00055 in 277082 control chromosomes in the gnomAD database, including 1 homozygote. The observed variant frequency is approximately 9-folds higher than the estimated maximal expected allele frequency for a pathogenic variant in MRE11A causing Hereditary Breast and Ovarian Cancer phenotype (6.3e-05). However, it does need to be noted that there is a pseudogene present on chromosome 3. The variant c.120C>T has been reported in the literature in individuals affected with breast cancer (Damiola_2014, Young_2016). These reports however do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign.
Athena Diagnostics Inc	RCV000857671	SCV001144536	benign	not provided	2018-09-27	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000524512	SCV001271864	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.
Sema4, Sema4	RCV000160575	SCV002538389	likely benign	Hereditary cancer-predisposing syndrome	2021-04-13	criteria provided, single submitter	curation
CeGaT Center for Human Genetics Tuebingen	RCV000857671	SCV004131306	likely benign	not provided	2024-01-01	criteria provided, single submitter	clinical testing	MRE11: BP4, BP7
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000857671	SCV004220912	benign	not provided	2023-06-21	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000524512	SCV000746007	likely benign	Ataxia-telangiectasia-like disorder 1	2016-01-24	no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000857671	SCV001965455	likely benign	not provided		no assertion criteria provided	clinical testing