NM_000251.3:c.2634+5G>A
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5
The NM_000251.3(MSH2):c.2634+5G>A variant causes a splice region, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 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 3 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD4 exome Cov.: 32
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Pathogenic:1Uncertain:1
The c.2634+5G>A intronic variant results from a G to A substitution 5 nucleotides after coding exon 15 in the MSH2 gene. This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis for this alteration is inconclusive; however, direct evidence is insufficient at this time (Ambry internal data). Based on the available evidence, the clinical significance of this variant remains unclear. -
This variant causes a G to A nucleotide substitution at the +5 position of intron 15 of the MSH2 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Two other single nucleotide substitutions with similar predicted splicing impact, c.2634+5G>C and c.2634+5G>T, have been shown to cause exon 15 skipping in patient RNA samples (PMID: 11074494, 18033691) and in minigene splicing assay (PMID: 18561205), respectively. To our knowledge, this variant has not been reported in functional studies nor in individuals affected with hereditary cancer in the literature. However, the two other variants at this position, c.2634+5G>C and c.2634+5G>T, have been reported in multiple Lynch syndrome families with DNA mismatch repair-deficient colorectal cancer (PMID: 11074494, 15713769, 16807412, 18561205, 31101557). In one family, the c.2634+5G>C variant segregated in 5 affected family members (PMID: 18033691). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Hereditary nonpolyposis colon cancer Pathogenic:1
Variant summary: MSH2 c.2634+5G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 5' splicing donor site. One predict the variant weakens a 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251350 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2634+5G>A has been reported in the literature in at least one individual affected with Hereditary Nonpolyposis Colorectal Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 35430768). ClinVar contains an entry for this variant (Variation ID: 1172006). In addition, other variants affecting this nucleotide (c.2634+5G>T, c.2634+5G>C) have been reported to associate with Hereditary Nonpolyposis Colorectal Cancer. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Hereditary nonpolyposis colorectal neoplasms Uncertain:1
This sequence change falls in intron 15 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 been observed in individual(s) with clinical features of MSH2-related conditions (PMID: 35430768). ClinVar contains an entry for this variant (Variation ID: 1172006). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant is associated with inconclusive levels of altered splicing (Invitae). 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.