chr2-47466747-C-T
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP6
The NM_000251.3(MSH2):c.1600C>T(p.Arg534Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,613,656 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R534H) has been classified as Likely benign.
Frequency
Consequence
NM_000251.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MSH2 | NM_000251.3 | c.1600C>T | p.Arg534Cys | missense_variant | 10/16 | ENST00000233146.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MSH2 | ENST00000233146.7 | c.1600C>T | p.Arg534Cys | missense_variant | 10/16 | 1 | NM_000251.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000460 AC: 7AN: 152102Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251364Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135864
GnomAD4 exome AF: 0.00000753 AC: 11AN: 1461554Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5AN XY: 727092
GnomAD4 genome AF: 0.0000460 AC: 7AN: 152102Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3AN XY: 74300
ClinVar
Submissions by phenotype
Lynch syndrome 1 Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Nov 25, 2015 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 05, 2023 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Mar 22, 2023 | This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. - |
Lynch syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 18, 2023 | This missense variant replaces arginine with cysteine at codon 534 of the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown conflicting results regarding the impact of this variant on mRNA splicing (PMID: 16995940, 18561205). This variant has been reported in an individual suspected of having Lynch syndrome (PMID: 18561205), and an individual affected with an unspecified cancer (PMID: 31391288). This variant has also been reported in a healthy individual lacking personal or family history of colorectal cancer (PMID: 26344056). This variant has been identified in 2/282752 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | University of Washington Department of Laboratory Medicine, University of Washington | May 01, 2018 | MSH2 NM_000251.2:c.1600C>T has a 76.9% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 0.16 to 1, generated from evidence of seeing this as a somatic mutation in a tumor with loss of heterozygosity at the MSH2 locus. See Shirts et al 2018, PMID 29887214. - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Oct 26, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 30, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual reported to have HNPCC, but was also observed in a control population without personal or family history of colorectal cancer (Tournier et al., 2008; Arora et al., 2015); Mini-gene splicing assays have shown this variant to cause partial or complete skipping of exon 10 (Lastella et al., 2006; Tournier et al., 2008); This variant is associated with the following publications: (PMID: 16995940, 22290698, 18561205, 9490293, 26344056, 30798936, 18822302, 9774676, 21120944, 34426522, 31391288, 14526391, 29887214) - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 02, 2022 | The p.R534C variant (also known as c.1600C>T), located in coding exon 10 of the MSH2 gene, results from a C to T substitution at nucleotide position 1600. The arginine at codon 534 is replaced by cysteine, an amino acid with highly dissimilar properties. A report in the literature suggests that this variant may have an effect on pre-mRNA splicing, by altering exonic splicing regulatory sequences. Additionally, this alteration was transfected into three different mammalian cell lines and a decrease in the exon inclusion levels in two of the three cell lines was seen (Lastella P et al. BMC Genomics. 2006 Sep;7:243). This alteration has also been reported to affect splicing by functional analysis using the ESE-dependent splicing assay (Tournier I et al. Hum. Mutat. 2008 Dec;29:1412-24). RNA studies have demonstrated this alteration does not result in abnormal splicing in the set of samples tested (Ambry internal data). This variant was identified in a tumor with LOH of MSH2, but authors suggested classifying as VUS following multifactorial analysis (Shirts BH et al. Am J Hum Genet, 2018 07;103:19-29). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 18, 2023 | This missense variant replaces arginine with cysteine at codon 534 of the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown conflicting results regarding the impact of this variant on mRNA splicing (PMID: 16995940, 18561205). This variant has been reported in an individual suspected of having Lynch syndrome (PMID: 18561205), and an individual affected with an unspecified cancer (PMID: 31391288). This variant has also been reported in a healthy individual lacking personal or family history of colorectal cancer (PMID: 26344056). This variant has been identified in 2/282752 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. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 23, 2024 | Variant summary: MSH2 c.1600C>T (p.Arg534Cys) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, core of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. 5/5 computational tools predict no significant impact on normal splicing. A functional study showed a decrease in inclusion of exon 10 in an in-vitro mini-gene assay perfromed in several cell lines (Lastella_2006). The variant allele was found at a frequency of 4e-06 in 251364 control chromosomes. c.1600C>T has been reported in the literature in individuals affected with cancer and in controls (example, Gorlov_2003, Arora_2015, Li_2020). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. The following publications have been ascertained in the context of this evaluation (PMID: 22290698, 26344056, 14526391, 16995940, 31391288, 18561205). ClinVar contains an entry for this variant (Variation ID: 90707). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. - |
Hereditary nonpolyposis colorectal neoplasms Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 08, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at