ClinVar Genomic variation as it relates to human health

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.

Observed in individuals undergoing hereditary cancer testing mostly for a personal or family history of breast/ovarian cancer (PMID: 26898890, 27878467, 31159747, 35534704); Published functional studies suggest that this variant impairs C1QBP binding (PMID: 31353207); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27363283, 31159747, 22829774, 26898890, 27878467, 31353207, 35534704)

Variant summary: MRE11 c.1727G>A (p.Arg576Gln) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00037 in 251374 control chromosomes, predominantly at a frequency of 0.00064 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 10 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 a benign polymorphism found primarily in populations of Latino origin. c.1727G>A has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome.A recent case-control study showed that this variant is not associated with breast cancer (Dorling_2021). Co-occurrence with a pathogenic variant has been reported (BRCA1 c.5359_5363delinsAGTGA, p.Cys1787_Gly1788delinsSerAsp), providing supporting evidence for a benign role. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign n=4, VUS n=3). Based on the evidence outlined above, the variant was classified as benign.

The MRE11 c.1727G>A variant is predicted to result in the amino acid substitution p.Arg576Gln. This variant has been reported in multigene testing of BRCA1 and BRCA2 negative patients, although no further evidence was provided to determine its pathogenicity (Yadav et al. 2017. PubMed ID: 27878467). This variant has also been reported in individuals with breast cancer (Table S5 - Tsaousis et al. 2019. PubMed ID: 31159747; Table S15 - Caminsky et al. 2016. PubMed ID: 26898890). In ClinVar, it is reported as benign, likely benign, and uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/127974/). This variant is reported in 0.22% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-94180441-C-T), which is higher than expected for a fully penetrant ataxia-telangiectasia-like disorder 1 pathogenic variant. Although we suspect this variant is benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

The MRE11 p.Arg576Gln variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs139461096) and ClinVar (reported likely benign and uncertain significance (5)). The c.1727G>A variant was identified in control databases in 96 of 282768 chromosomes at a frequency of 0.00034 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 23 of 10368 chromosomes (freq: 0.002218), Other in 7 of 7222 chromosomes (freq: 0.000969), Latino in 23 of 35436 chromosomes (freq: 0.000649), European (non-Finnish) in 35 of 129138 chromosomes (freq: 0.000271), South Asian in 6 of 30614 chromosomes (freq: 0.000196) and African in 2 of 24968 chromosomes (freq: 0.00008); it was not observed in the East Asian or European (Finnish) populations. The p.Arg576 residue is not conserved in mammals and five of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, and MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.