rs759130031
Variant summary
Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1PP3_StrongPP5_Very_Strong
The NM_005591.4(MRE11):c.659+1G>A variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000625 in 1,599,742 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_005591.4 splice_donor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 20 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MRE11 | NM_005591.4 | c.659+1G>A | splice_donor_variant | ENST00000323929.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MRE11 | ENST00000323929.8 | c.659+1G>A | splice_donor_variant | 1 | NM_005591.4 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152136Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 250724Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135512
GnomAD4 exome AF: 0.00000622 AC: 9AN: 1447606Hom.: 0 Cov.: 28 AF XY: 0.00000832 AC XY: 6AN XY: 721082
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152136Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74330
ClinVar
Submissions by phenotype
Ataxia-telangiectasia-like disorder 1 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 12, 2024 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jul 18, 2016 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 03, 2021 | The c.659+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 6 of the MRE11A gene. This alteration was detected in a patient with a disorder resembling a Nijmegen breakage syndrome-like severe microcephaly but without reported immunodeficiency. The authors performed RT-PCR and sequencing analysis which demonstrated that this mutation results in exon 7 skipping leading to premature protein truncation (Matsumoto Y et al. DNA Repair (Amst.). 2011 Mar;10:314-21). This alteration was also detected in 1/230 unselected Japanese women with ovarian cancer (Hirasawa A et al. Oncotarget. 2017 Dec;8:112258-112267). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. - |
Ataxia-telangiectasia-like disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 22, 2023 | For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site results in skipping of exon 7 and introduces a premature termination codon (PMID: 21227757). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 230014). Disruption of this splice site has been observed in individual(s) with Nijmegen breakage syndrome-like severe microcephaly or ovarian cancer (PMID: 21227757, 29348823). This variant is present in population databases (rs759130031, gnomAD 0.03%). This sequence change affects a donor splice site in intron 7 of the MRE11 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. - |
MRE11-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 02, 2023 | The MRE11 c.659+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant has been reported in individuals with ovarian cancer and/or a family history of cancer (Hirasawa et al. 2017. PubMed ID: 29348823; Table S1, Shao et al. 2019. PubMed ID: 31742824). However, in a study of individuals with pancreatic cancer, this variant was only reported in control subjects (eTable 3, Hu et al. 2018. PubMed ID: 29922827). This variant was also reported in the compound heterozygous state in a patient with Nijmegen breakage syndrome-like severe microcephaly (Patient 1, Matsumoto et al. 2011. PubMed ID: 21227757). This variant is reported in 0.027% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-94209454-C-T) and is reported as pathogenic/likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/230014/). Variants that disrupt the consensus splice donor site in MRE11 are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at