rs587779187
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_001258281.1(MSH2):c.-95dupA variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000352 in 1,418,440 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_001258281.1 5_prime_UTR
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152258Hom.: 0 Cov.: 33
GnomAD4 exome AF: 0.00000237 AC: 3AN: 1266064Hom.: 0 Cov.: 20 AF XY: 0.00000159 AC XY: 1AN XY: 630418
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152376Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74512
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2
The c.-81dupA variant is located in the 5 prime untranslated region (5'UTR) of the MSH2 gene. This variant results from an duplication of an A nucleotide 81 nucleotides upstream from the first translated codon. This alteration has been reported (designated as "80A insertion") in a Korean family, including a mother with colon cancer at 61 years of age, and her son diagnosed with rectal cancer at age 36, and was not reported in any of the 157 members of the nonmalignant control group (Shin YK et al. Hum. Mutat., 2004 Oct;24:351; Shin KH et al. Cancer Res., 2002 Jan;62:38-42). Shin et al. also showed that this alteration resulted in decreased transcriptional efficiency by 82%, speculating this may be due to its proximity to the major transcription start point. This nucleotide position is poorly conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
This variant is located in the 5’ untranslated region of the MSH2 gene. Splice site prediction tools suggest that this variant may not impact RNA splicing. Functional studies have shown that this variant had 18% promoter activity compared to the wild type by luciferase reporter assay and loss of MSH2 expression from mutant allele (PMID: 11782355). This variant has been reported in individuals affected with colorectal cancer (PMID: 11782355). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Lynch syndrome 1 Uncertain:1
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Lynch syndrome Uncertain:1
This variant is located in the 5' untranslated region of the MSH2 gene. Splice site prediction tools suggest that this variant may not impact RNA splicing. Functional studies have shown that this variant had 18% promoter activity compared to the wild type by luciferase reporter assay and loss of MSH2 expression from mutant allele (PMID: 11782355). This variant has been reported in individuals affected with colorectal cancer (PMID: 11782355). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
not provided Uncertain:1
In the published literature, the variant has been reported in a family with colorectal cancer (PMIDs: 11782355 (2002) and 15365995 (2004)). Functional studies have shown that this variant results in a reduced transcriptional efficiency in a luciferase reporter assay and loss of MSH2 expression from the mutant allele (PMID: 11782355 (2002)). The frequency of this variant in the general population, 0.000013 (2/152258 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Based on the available information, we are unable to determine the clinical significance of this variant. -
Muir-Torré syndrome;C2936783:Lynch syndrome 1;C5436806:Mismatch repair cancer syndrome 2 Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at