rs397515879
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_ModerateBP6BP7
The NM_000251.3(MSH2):c.51C>A(p.Val17=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000691 in 1,446,562 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V17V) has been classified as Likely benign.
Frequency
Consequence
NM_000251.3 synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MSH2 | NM_000251.3 | c.51C>A | p.Val17= | synonymous_variant | 1/16 | ENST00000233146.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MSH2 | ENST00000233146.7 | c.51C>A | p.Val17= | synonymous_variant | 1/16 | 1 | NM_000251.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 exomes AF: 0.0000183 AC: 4AN: 218502Hom.: 0 AF XY: 0.0000168 AC XY: 2AN XY: 119174
GnomAD4 exome AF: 0.00000691 AC: 10AN: 1446562Hom.: 0 Cov.: 31 AF XY: 0.00000418 AC XY: 3AN XY: 718364
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | May 01, 2024 | MSH2: BP4, BP7 - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Oct 07, 2022 | To the best of our knowledge, the variant has not been reported in the published literature. The frequency of this variant in the general population, 0.000031 (3/97280 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on MSH2 mRNA splicing yielded predictions that this variant may result in the gain of a cryptic splice site without affecting the natural splice sites . Based on the available information, we are unable to determine the clinical significance of this variant. - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 05, 2023 | The c.51C>A variant (also known as p.V17V), located in coding exon 1 of the MSH2 gene, results from a C to A substitution at nucleotide position 51. This nucleotide substitution does not change the valine at codon 17 but may have some effect on normal mRNA splicing. In silico splice site analysis for this alteration is inconclusive; however, direct evidence is insufficient at this time (Ambry internal data). This nucleotide position is not well conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 26, 2018 | - - |
Hereditary nonpolyposis colorectal neoplasms Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | This sequence change affects codon 17 of the MSH2 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the MSH2 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. It is unclear whether an alternative in-frame methionine located at codon 26 has the potential to rescue this variant. This variant is present in population databases (rs397515879, gnomAD 0.004%). 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: 186237). Studies have shown that this variant results in activation of a cryptic splice site and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. Reports on variants that affect the MSH2 initiator codon, c.1A>C and c.1A>T, indicate that Met26 may serve as an alternate initiator codon (PMID: 21837758, 9718327, 18781192). An experimental study of a recombinant MSH2 protein lacking the first 25 amino acid residues has shown that the truncated protein remains partially functional (PMID: 21837758). The clinical significance of these findings is unknown. 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. - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jul 06, 2017 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Lynch syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | May 31, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at