NM_000251.3:c.942+3A>C
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP5
The NM_000251.3(MSH2):c.942+3A>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000251.3 splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 0
GnomAD4 exome Cov.: 0
GnomAD4 genome Cov.: 0
ClinVar
Submissions by phenotype
Lynch syndrome 1 Pathogenic:2
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This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 8062247]. -
not provided Pathogenic:1
Not observed in large population cohorts (Lek 2016); In silico analysis supports a deleterious effect on splicing; Has not been previously published as pathogenic or benign to our knowledge -
Hereditary cancer-predisposing syndrome Pathogenic:1
The c.942+3A>C intronic variant results from an A to C substitution 3 nucleotides after coding exon 5 in the MSH2 gene. This variant was identified in an individual whose early onset, MSI-H colon tumor demonstrated absent MSH2 and MSH6 by immunohistochemistry (IHC) along with a somatic pathogenic mutation in MSH2 (Ambry internal data). While this exact alteration has not been reported in the literature, an alteration at the same nucleotide position (c.942+3A>T) has been reported in numerous individuals meeting clinical diagnostic criteria for Lynch syndrome and has been shown by multiple functional studies to cause exon 5 skipping (South CD et al. J. Natl. Cancer Inst. 2008 Feb;100(4):277-81; Desai DC et al. J. Med. Genet. 2000 Sep;37(9):646-52; Arnold S et al. Hum. Mutat. 2009 May;30(5):757-70; Auclair J et al. Hum. Mutat. 2006 Feb;27(2):145-54; Casey G et al. JAMA. 2005 Feb;293(7):799-809; Chong G et al. Hum. Mutat. 2009 Aug;30(8):E797-812). Furthermore, RNA studies have demonstrated a different alteration at this same position (c.942+3A>G) results in abnormal splicing as well (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Hereditary nonpolyposis colorectal neoplasms Uncertain:1
This sequence change falls in intron 5 of the MSH2 gene. It does not directly change the encoded amino acid sequence of the MSH2 protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MSH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1200813). 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. This variant disrupts the c.942+3 nucleotide in the MSH2 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 8062247, 10978353, 15222003, 16395668, 19419416, 20682701, 21681552, 22883484, 24310308). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.