rs587779168
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6
The NM_000251.3(MSH2):c.645+3A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,613,580 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, intron
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152230Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000120 AC: 3AN: 250270Hom.: 0 AF XY: 0.00000739 AC XY: 1AN XY: 135382
GnomAD4 exome AF: 0.0000137 AC: 20AN: 1461350Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8AN XY: 727012
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152230Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2AN XY: 74380
ClinVar
Submissions by phenotype
not specified Uncertain:2Benign:2
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Mar 04, 2025 | Classification criteria: BP4_supp - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Aug 04, 2016 | 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. - |
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 11, 2021 | Variant summary: MSH2 c.645+3A>G alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. This has been further corroborated by RNA studies demonstrating no abnormal splicing leading to its re-classification as a likely benign variant (Karam_2019). The variant allele was found at a frequency of 1.2e-05 in 250270 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.645+3A>G has been reported in the literature among individuals undergoing multigene panel testing for hereditary cancer (example, Kiyozumi_2019, Karam_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=3, VUS, n=2). Based on the evidence outlined above, the variant was classified as likely benign. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 06, 2017 | The c.645+3A>G variant in MSH2 has not been previously reported in individuals w ith Lynch syndrome but has been identified in 1/8640 of East Asian chromosomes b y the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs587779168). This variant is located in the 5' splice region. Computational too ls do not suggest an impact to splicing. However, this information is not predic tive enough to rule out pathogenicity. In addition, this variant was classified as a variant of uncertain significance on Sept. 5, 2013 by the ClinGen-approved InSiGHT expert panel (SCV000107696.2). In summary, the clinical significance of the c.645+3A>G variant is uncertain. - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 24, 2023 | This variant causes an A to G nucleotide substitution at the +3 position of intron 3 of the MSH2 gene. An RNA study performed demonstrated this variant had no impact on RNA splicing (PMID: 31642931). This variant has been reported in an individual affected with an unspecified cancer (PMID: 31386297). This variant has been identified in 3/250270 chromosomes 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. - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 20, 2018 | 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. - |
Lynch syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Aug 15, 2023 | - - |
Lynch syndrome 1 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Aug 20, 2024 | This variant is considered likely benign. This variant is intronic and is not expected to impact mRNA splicing. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 27363726]. - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jun 29, 2023 | - - |
Hereditary nonpolyposis colorectal neoplasms Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 23, 2025 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at