2-47463027-G-C
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6
The NM_000251.3(MSH2):c.1387-4G>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000174 in 1,613,344 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000251.3 splice_region, splice_polypyrimidine_tract, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MSH2 | NM_000251.3 | c.1387-4G>C | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | ENST00000233146.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MSH2 | ENST00000233146.7 | c.1387-4G>C | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | 1 | NM_000251.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000105 AC: 16AN: 152104Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000279 AC: 7AN: 251176Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135786
GnomAD4 exome AF: 0.00000821 AC: 12AN: 1461240Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6AN XY: 726956
GnomAD4 genome AF: 0.000105 AC: 16AN: 152104Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8AN XY: 74318
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:2
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 28, 2016 | Variant summary: The MSH2 c.1387-4G>C variant involves the alteration of a non-conserved intronic nucleotide with 4/5 splice prediction tools predict no significant impact on normal splicing and ESE finder predicts alterations to ESE binding, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 5/120968 (1/24195), predominantly in the African cohort, 5/10274 (1/2054), which does not exceed the estimated maximal expected allele frequency for a pathogenic MSH2 variant of 1/1759. The variant of interest, to our knowledge, has not been reported in affected individuals via publications, although a clinical diagnostic laboratory has cited the variant as "uncertain significance." Therefore, until additional information becomes available, the variant of interest has been classified as a "Variant of Uncertain Significance (VUS)." - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 03, 2015 | - - |
Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Dec 16, 2022 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Oct 16, 2015 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 03, 2019 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Jan 01, 2022 | - - |
MSH2-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 11, 2022 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Hereditary nonpolyposis colorectal neoplasms Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 05, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at