2-47799722-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate
The NM_000179.3(MSH6):c.1739C>T(p.Ser580Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000125 in 1,614,078 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/20 in silico tools predict a damaging outcome for this variant. 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. S580W) has been classified as Likely benign.
Frequency
Consequence
NM_000179.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MSH6 | NM_000179.3 | c.1739C>T | p.Ser580Leu | missense_variant | 4/10 | ENST00000234420.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MSH6 | ENST00000234420.11 | c.1739C>T | p.Ser580Leu | missense_variant | 4/10 | 1 | NM_000179.3 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152082Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000559 AC: 14AN: 250246Hom.: 0 AF XY: 0.0000663 AC XY: 9AN XY: 135686
GnomAD4 exome AF: 0.000135 AC: 198AN: 1461878Hom.: 0 Cov.: 34 AF XY: 0.000133 AC XY: 97AN XY: 727240
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152200Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74396
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 21, 2023 | Observed in individuals with colorectal cancer, including some with tumor studies that were not consistent with MSH6-related Lynch syndrome, and in individuals with breast cancer (Barnetson et al., 2008; Devlin et al., 2008; Hampel et al., 2018; Rosenthal et al., 2018; Dorling et al., 2021); Published functional studies demonstrate reduced MMR activity compared to wild type (Drost et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24362816, 26333163, 23621914, 22949387, doi:10.5923/j.bioinformatics.20160602.03, 27527004, 29596542, 17531815, 21120944, 34288098, 30267214, 34687117, 31391288, 32980694, 33471991, 18033691, 18269114, 31965077, 19389263) - |
Likely pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Nov 17, 2022 | The frequency of this variant in the general population, 0.000098 (3/30616 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, this variant has been reported in individual with Lynch syndrome (PMID: 18269114 (2008)), colorectal cancer (PMID: 18033691 (2008)), and breast cancer (PMID: 33471991 (2021)). The variant has also been reported in unaffected individuals (PMID: 33471991 (2021)). An invitro functional study has reported that this variant reduced mismatch repair efficiency (PMID: 31965077 (2020)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. - |
Hereditary cancer-predisposing syndrome Uncertain:3
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Jan 02, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 07, 2022 | The p.S580L variant (also known as c.1739C>T), located in coding exon 4 of the MSH6 gene, results from a C to T substitution at nucleotide position 1739. The serine at codon 580 is replaced by leucine, an amino acid with dissimilar properties. This variant has been identified in individuals diagnosed with colorectal cancer (Barnetson RA et al. Hum. Mutat. 2008 Mar;29:367-74; Rosenthal EA et al. Hum Genet, 2018 Oct;137:795-806). This variant has also been reported in a HNPCC-like family; however, no other clinical information was provided (Devlin LA et al. Ulster Med J. 2008 Jan;77:25-30). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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 | Nov 22, 2023 | This missense variant replaces serine with leucine at codon 580 of the MSH6 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with Lynch syndrome-associated cancer, in which one tumor was found to have stable microsatellite markers and had detectable DNA mismatch repair proteins (PMID: 18033691, 18269114). This variant also has been reported in a pancreatic cancer case-control study in 2 unaffected controls and absent in 1005 cancer cases (PMID: 32980694) and a breast cancer case-control study in 5 breast cancer cases and 8 unaffected controls (PMID: 33471991). This variant has been identified in 16/281632 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:2
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 21, 2022 | Variant summary: MSH6 c.1739C>T (p.Ser580Leu) results in a non-conservative amino acid change located in the connector domain (IPR007860) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 297806 control chromosomes (gnomAD and publication). This frequency is not significantly higher than expected for a pathogenic variant in MSH6 causing Lynch Syndrome (6e-05 vs 0.00014), allowing no conclusion about variant significance. c.1739C>T has been reported in the literature in at least one individual with an HNPCC-like classification not meeting Amsterdam criteria, in an individual affected with colorectal cancer at <55 years of age, but with a microsatellite stable tumor which was positive for MSH6, MSH2 and MLS1 by immunohistochemistry, and as a VUS in an individual affected with a cancer within the Hereditary Nonpolyposis Colorectal Cancer (HNPCC)/Lynch syndrome spectrum (e.g. Devlin_2008, Barnetson_2008, Li_2020). These reports do not provide unequivocal conclusions about association of the variant with HNPCC/Lynch Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function (e.g. Drost_2020). The variant was found to have a MMR activity 10-30% of normal, determined by CIMRA assay. Seven submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jul 14, 2019 | - - |
Endometrial carcinoma;C1833477:Lynch syndrome 5;C5436807:Mismatch repair cancer syndrome 3 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 16, 2022 | - - |
Endometrial carcinoma Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Jun 26, 2023 | - - |
Lynch syndrome 5 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Mar 14, 2024 | 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: 27363726]. - |
Hereditary nonpolyposis colorectal neoplasms Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Dec 26, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at