rs144896235
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2
The NM_005591.4(MRE11):āc.1667A>Gā(p.Asn556Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000146 in 1,614,134 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N556D) has been classified as Likely benign.
Frequency
Consequence
NM_005591.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MRE11 | NM_005591.4 | c.1667A>G | p.Asn556Ser | missense_variant | 15/20 | ENST00000323929.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MRE11 | ENST00000323929.8 | c.1667A>G | p.Asn556Ser | missense_variant | 15/20 | 1 | NM_005591.4 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.000171 AC: 26AN: 152160Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.000123 AC: 31AN: 251258Hom.: 0 AF XY: 0.000162 AC XY: 22AN XY: 135792
GnomAD4 exome AF: 0.000143 AC: 209AN: 1461856Hom.: 0 Cov.: 31 AF XY: 0.000149 AC XY: 108AN XY: 727234
GnomAD4 genome ? AF: 0.000171 AC: 26AN: 152278Hom.: 0 Cov.: 31 AF XY: 0.000161 AC XY: 12AN XY: 74468
ClinVar
Submissions by phenotype
Ataxia-telangiectasia-like disorder 1 Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 22, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 23, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | 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. - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Nov 16, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 19, 2023 | The p.N556S variant (also known as c.1667A>G), located in coding exon 14 of the MRE11A gene, results from an A to G substitution at nucleotide position 1667. The asparagine at codon 556 is replaced by serine, an amino acid with highly similar properties. This variant was reported in 5/1313 early-onset breast cancer cases and 0/1123 population controls (Damiola F et al. Breast Cancer Res. 2014 Jun;16:R58). This amino acid position is poorly 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. - |
not provided Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Nov 22, 2019 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Nov 22, 2019 | - - |
Ataxia-telangiectasia-like disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 25, 2022 | This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 556 of the MRE11 protein (p.Asn556Ser). This variant is present in population databases (rs144896235, gnomAD 0.03%). This missense change has been observed in individual(s) with breast cancer (PMID: 24894818). ClinVar contains an entry for this variant (Variation ID: 142425). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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. - |
MRE11-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 06, 2023 | The MRE11 c.1667A>G variant is predicted to result in the amino acid substitution p.Asn556Ser. This variant was reported in five cases of early onset breast cancer (diagnosed at or before age 45) and was absent in controls in this cohort study (Damiola F et al 2014. PubMed ID: 24894818). This variant was also reported as a variant of uncertain significance in an individual with hepatoblastoma (Table 3 Aguiar et al 2022. PubMed ID: 35495172). This variant is reported in 0.023% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-94180501-T-C) and is reported in ClinVar by most other laboratories as uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/142425/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at