Submissions for variant NM_005591.4(MRE11):c.2070+2T>A

gnomAD frequency: 0.00001  dbSNP: rs786202801

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165802	SCV000216549	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-06-27	criteria provided, single submitter	clinical testing	The c.2070+2T>A intronic variant results from a T to A substitution two nucleotides after coding exon 18 in the MRE11A gene. This nucleotide position is highly conserved in available vertebrate species. This variant was observed in 1/287 patients with hereditary breast and/or ovarian cancer; this patient was diagnosed with breast cancer at age 54 and had a family history of breast and ovarian cancer (Caminsky NG et al. Hum Mutat, 2016 07;37:640-52). In silico splice site analysis predicts that this alteration will weaken the native splice donor site and may result in the creation or strengthening of a novel splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein. Although this alteration is located in the last intron, a disruption of splicing here would likely impact the DNA binding domain located at the C-terminal end of the MRE11A protein (Damiola F et al. Breast Cancer Res., 2014 Jun;16:R58; Usui T et al. Cell, 1998 Nov;95:705-16). As such, this alteration is classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000642458	SCV000764137	uncertain significance	Ataxia-telangiectasia-like disorder	2023-10-08	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 19 of the MRE11 gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is present in population databases (rs786202801, gnomAD 0.003%). Disruption of this splice site has been observed in individual(s) with breast cancer (PMID: 24894818, 26898890). ClinVar contains an entry for this variant (Variation ID: 186243). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
Baylor Genetics	RCV003468758	SCV004193809	likely pathogenic	Ataxia-telangiectasia-like disorder 1	2023-08-19	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV003480069	SCV004226221	uncertain significance	not provided	2023-01-17	criteria provided, single submitter	clinical testing	PM2, PVS1_moderate
Dr. Peter K. Rogan Lab, Western University	RCV000416696	SCV000262590	likely pathogenic	Hereditary breast ovarian cancer syndrome	2015-12-22	no assertion criteria provided	research	Sequenced patient with familial breast cancer