2-47803473-C-T
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Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PP3PP5_Very_Strong
The NM_000179.3(MSH6):c.3226C>T(p.Arg1076Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000502 in 1,613,938 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★★).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000053 ( 0 hom. )
Consequence
MSH6
NM_000179.3 missense
NM_000179.3 missense
Scores
6
10
3
Clinical Significance
Conservation
PhyloP100: 3.14
Genes affected
MSH6 (HGNC:7329): (mutS homolog 6) This gene encodes a member of the DNA mismatch repair MutS family. In E. coli, the MutS protein helps in the recognition of mismatched nucleotides prior to their repair. A highly conserved region of approximately 150 aa, called the Walker-A adenine nucleotide binding motif, exists in MutS homologs. The encoded protein heterodimerizes with MSH2 to form a mismatch recognition complex that functions as a bidirectional molecular switch that exchanges ADP and ATP as DNA mismatches are bound and dissociated. Mutations in this gene may be associated with hereditary nonpolyposis colon cancer, colorectal cancer, and endometrial cancer. Transcripts variants encoding different isoforms have been described. [provided by RefSeq, Jul 2013]
FBXO11 (HGNC:13590): (F-box protein 11) This gene encodes a member of the F-box protein family which is characterized by an approximately 40 amino acid motif, the F-box. The F-box proteins constitute one of the four subunits of ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), which function in phosphorylation-dependent ubiquitination. The F-box proteins are divided into 3 classes: Fbws containing WD-40 domains, Fbls containing leucine-rich repeats, and Fbxs containing either different protein-protein interaction modules or no recognizable motifs. The protein encoded by this gene belongs to the Fbxs class. It can function as an arginine methyltransferase that symmetrically dimethylates arginine residues, and it acts as an adaptor protein to mediate the neddylation of p53, which leads to the suppression of p53 function. This gene is known to be down-regulated in melanocytes from patients with vitiligo, a skin disorder that results in depigmentation. Polymorphisms in this gene are associated with chronic otitis media with effusion and recurrent otitis media (COME/ROM), a hearing loss disorder, and the knockout of the homologous mouse gene results in the deaf mouse mutant Jeff (Jf), a single gene model of otitis media. Alternatively spliced transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jun 2010]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.835
PP5
Variant 2-47803473-C-T is Pathogenic according to our data. Variant chr2-47803473-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 89357.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47803473-C-T is described in Lovd as [Likely_pathogenic]. Variant chr2-47803473-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| MSH6 | NM_000179.3 | c.3226C>T | p.Arg1076Cys | missense_variant | 5/10 | ENST00000234420.11 | NP_000170.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| MSH6 | ENST00000234420.11 | c.3226C>T | p.Arg1076Cys | missense_variant | 5/10 | 1 | NM_000179.3 | ENSP00000234420 | P4 |
Frequencies
GnomAD3 genomes 0.0000197 AC: 3AN: 152064Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000955 AC: 24AN: 251346Hom.: 0 AF XY: 0.000103 AC XY: 14AN XY: 135842
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GnomAD4 exome AF: 0.0000534 AC: 78AN: 1461874Hom.: 0 Cov.: 33 AF XY: 0.0000619 AC XY: 45AN XY: 727236
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GnomAD4 genome 0.0000197 AC: 3AN: 152064Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74274
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ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:29
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Lynch syndrome 5 Pathogenic:6
| Likely pathogenic, criteria provided, single submitter | clinical testing | Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine | Oct 15, 2017 | This c.3226C>T (p.Arg1076Cys) variant in the MSH6 gene has been reported in the homozygous state in 1 individual with colorectal cancer (PMID: 22250089). It has also been reported in trans configuration with a pathogenic variant in 3 unrelated individuals with autosomal recessive hereditary nonpolyposis colorectal cancer type 5 (HNPCC5; PMID: 16418736, 16525781, 18409202) and in 2 related individuals with mismatch repair cancer syndrome (MMRCS; MIM 600678; PMID: 21039432). Segregation studies in this family confirmed that the c.3226C>T (p.Arg1076Cys) variant segregated together with a second pathogenic variant in the 2 affected individuals, but not in 6 unaffected family members (PMID: 21039432). The c.3226C>T variant is very rare in the general population. While not validated for clinical use, the computer-based algorithms PolyPhen-2 and SIFT predict the p.Arg1076Cys change to be deleterious. Based on this information, the c.3226C>T (p.Arg1076Cys) variant in the MSH6 gene is classified as likely pathogenic. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Oct 04, 2021 | - - |
| Likely pathogenic, criteria provided, single submitter | research | HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology | Sep 11, 2018 | - - |
| Likely pathogenic, no assertion criteria provided | clinical testing | University of Washington Department of Laboratory Medicine, University of Washington | Jun 21, 2019 | This variant is present in the ClinVar database (ID: 89357) and is classified as likely pathogenic. It has been seen in individuals with constitutional mismatch repair deficiency (CMMRD) in conjunction with a second MSH6 mutation (Rahner 2008). In the heterozygous state, it has been seen in individuals with cancer however may be associated with a lower risk (hypomorphic) for cancer than other pathogenic MSH6 mutations (Rahner 2008). - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Jun 25, 2021 | - - |
not provided Pathogenic:6
| Likely pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Jul 31, 2024 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2023 | MSH6: PM3:Strong, PM2, PS4:Moderate, PM5:Supporting - |
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Sep 23, 2022 | The frequency of this variant in the general population, 0.00027 (5/18386 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in multiple individuals with Lynch syndrome (PMID: 18566915 (2009), 26832770 (2016), 27601186 (2016), 18566915 (2009)), breast cancer (PMID: 32658311 (2021), 34637943 (2021)), prostate cancer (PMID: 32832836 (2020), or a Lynch syndrome associated cancer (PMID: 32635641 (2020), 30521064 (2019), 30322717 (2018), 27398995 (2016), 27696107 (2016), 19072991 (2009)). The variant has also been reported in the compound heterozygous state with other pathogenic MSH6 variants in individuals with a constitutional mismatch repair deficiency (CMMRD) syndrome phenotype (PMID: 21039432 (2011), 18409202 (2008), 16418736 (2006), 16525781 (2006)). Additionally, this variant has been shown to result in defective DNA repair when the variant is in the homozygous state or when coupled with another pathogenic MSH6 variant (PMID: 22250089 (2012)). Based on the available information, this variant is classified as pathogenic with reduced penetrance. This individual is at increased risk of developing MSH6 related cancers, though he/she is likely to have less cancer risk than individuals who are positive for other MSH6 pathogenic variants. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Aug 18, 2023 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 08, 2023 | Observed in individuals with a personal and/or family history of colorectal cancer, some with tumor studies demonstrating loss of MSH6 protein expression (Nilbert et al., 2009; Schofield et al., 2009; Limburg et al., 2011; Rubio et al., 2016; Schultheis et al., 2016; Liccardo et al., 2017; Rohlin et al., 2017; Xu et al., 2020); May be a hypomorphic allele as it was observed in the homozygous state in a patient with relatively late onset colorectal cancer, and, among heterozygotes, a limited number of Lynch-associated cancers have been observed in multiple internal and published families (Okkels et al., 2006; Rahner et al., 2008; Gardes et al., 2012); 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: 22949379, 15483016, 20531397, 22886683, 32980694, 31830689, 34637943, 29922827, 28888541, 32832836, 32029870, 33194656, 17531815, 21120944, 23621914, 18566915, 21674763, 21056691, 16525781, 16418736, 18409202, 19072991, 21039432, 26832770, 24012250, 27398995, 22250089, 18709565, 27601186, 27696107, 29785566, 28481244, 21836479, 22495361, 21376568, 30521064, 30322717, 32635641, 31721094, 31997046, 31447099, 32658311, 33422121, 31589614, 33309985, 34308104, 34873480, 35725860, 32719484, 30787465, 33087929, 32427313, 34445333, 33365374, 35535697) - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Dec 24, 2020 | The MSH6 c.3226C>T; p.Arg1076Cys variant (rs63750617) is reported in the literature in multiple heterozygous individuals affected with Lynch syndrome (Lagerstedt-Robinson 2016, Liccardo 2017, Schofield 2009). This variant has also been reported in trans to another pathogenic variant in multiple individuals with symptoms consistent with constitutional mismatch repair deficiency (CMMRD) syndrome (Gardes 2012, Jasperson 2011, Okkels 2006, Plaschke 2006). However, the p.Arg1076Cys variant has also been found in a homozygous individual with symptoms more consistent with Lynch syndrome (Gardes 2012), as well as in healthy heterozygous relatives of affected individuals (Jasperson 2011, Okkels 2006, Plaschke 2006), suggesting it may exhibit incomplete penetrance. This variant is found in the general population with a low overall allele frequency of 0.01% (24/251346 alleles) in the Genome Aggregation Database. The arginine at codon 1076 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.849). Patient cells carrying this variant exhibit reduced resolution of irradiation-induced DNA damage foci compared to control cells (Gardes 2012), suggesting reduced DNA damage repair activity. Based on available information, this variant is considered to be likely pathogenic. References: Gardes P et al. Human MSH6 deficiency is associated with impaired antibody maturation. J Immunol. 2012 Feb 15;188(4):2023-9. Jasperson KW et al. Constitutional mismatch repair-deficiency syndrome presenting as colonic adenomatous polyposis: clues from the skin. Clin Genet. 2011 Oct;80(4):394-7. Lagerstedt-Robinson K et al. Mismatch repair gene mutation spectrum in the Swedish Lynch syndrome population. Oncol Rep. 2016 Nov;36(5):2823-2835. Liccardo R, De Rosa M, Rossi GB, Carlomagno N, Izzo P, Duraturo F. Incomplete Segregation of MSH6 Frameshift Variants with Phenotype of Lynch Syndrome. Int J Mol Sci. 2017 May 6;18(5):999. Okkels H et al. Polyposis and early cancer in a patient with low penetrant mutations in MSH6 and APC: hereditary colorectal cancer as a polygenic trait. Int J Colorectal Dis. 2006 Dec;21(8):847-50. Plaschke J et al. Compound heterozygosity for two MSH6 mutations in a patient with early onset of HNPCC-associated cancers, but without hematological malignancy and brain tumor. Eur J Hum Genet. 2006 May;14(5):561-6. Schofield L et al. Population-based detection of Lynch syndrome in young colorectal cancer patients using microsatellite instability as the initial test. Int J Cancer. 2009 Mar 1;124(5):1097-102. - |
Lynch syndrome 1 Pathogenic:3
| Likely pathogenic, reviewed by expert panel | curation | International Society for Gastrointestinal Hereditary Tumours (InSiGHT) | Mar 09, 2018 | Co-occurrence in trans with a known pathogenic sequence variant in the same gene in a patient with clinical features consistent with CMMRD and documented MMR deficiency in normal cells - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Department of Molecular Diagnostics, Institute of Oncology Ljubljana | Apr 02, 2020 | - - |
| Likely pathogenic, criteria provided, single submitter | research | Laan Lab, Human Genetics Research Group, University of Tartu | May 01, 2021 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:3
| Likely pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jul 06, 2023 | This missense variant replaces arginine with cysteine at codon 1076 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 heterozygous state in multiple individuals and families affected with Lynch syndrome-associated cancer (PMID: 18566915, 19072991, 21056691, 22949379, 27696107, 28481244, 30521064). This variant has been reported in at least five individuals found in trans with pathogenic MSH6 co-variants (compound heterozygous) who were affected with early-onset mismatch repair deficient colorectal cancer and/or polyps and some features of constitutional mismatch repair deficiency (CMMR-D) syndrome (PMID: 16418736, 16525781, 18409202, 21039432, 21836479, 22250089, 29785566). This variant was also detected in a homozygous individual affected with recurrent colorectal cancer in his 40s and multiple colorectal adenomas and polyps (PMID: 22250089). This variant has been identified in 24/251346 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 13, 2021 | The p.R1076C pathogenic mutation (also known as c.3226C>T), located in coding exon 5 of the MSH6 gene, results from a C to T substitution at nucleotide position 3226. The arginine at codon 1076 is replaced by cysteine, an amino acid with highly dissimilar properties. The in silico prediction for this alteration is inconclusive and this amino acid position is highly conserved in available vertebrate species. In one study, the p.R1076C mutation was detected in a male proband with colorectal cancer (CRC) at age 55 and a previous diagnosis of gastric cancer. The colorectal tumor of the proband demonstrated clonal loss of expression of both MSH2 and MSH6 proteins by immunohistochemistry (IHC). In addition, this individual's family history included a brother with CRC, an aunt with ovarian cancer, and a cousin with endometrial cancer (Schofield L et al. Int. J .Cancer. 2009 Sep;125:1492-3). The p.R1076C mutation was also reported in a 46-year-old man diagnosed with ascending colon cancer, but his tumor IHC testing showed intact staining for the MLH1, MSH2, and MSH6 proteins (Limburg PJ et al. Clin. Gastroenterol. Hepatol. 2011 Jun;9:497-502). Furthermore, the p.R1076C mutation was identified in a proband with a microsatellite stable endometrial cancer with intact staining for the MLH1, MSH2, and MSH6 proteins on IHC (Rubio I et al. Oncology. 2016 Jul;91(3):171-6). In addition, this mutation has been identified in multiple individuals whose Lynch syndrome-associated tumors displayed high microsatellite instability and/or had isolated loss of MSH6 on immunohistochemistry (IHC); however, at least two probands had intact staining on IHC (Ambry internal data). At least five individuals with features of CMMR-D have been reported to carry the p.R1076C mutation and a pathogenic (nonsense/frameshift) MSH6 mutation in trans, suggesting biallelic mismatch repair inactivation (Plaschke J et al. Eur. J. Hum. Genet. 2006 May;14:561-6; Okkels H et al. Int. J. Colorectal Dis. 2006 Dec;21:847-50; Rahner N et al. Am. J. Med. Genet. A. 2008 May;146A:1314-9; Jasperson KW et al. Clin. Genet. 2011 Oct;80:394-7). However, an individual found to be homozygous for this mutation did not present with classic CMMR-D symptoms and instead developed CRC at the ages of 45 and 49, suggesting that this variant may be hypomorphic. As risk estimates are unknown at this time, clinical correlation is advised. Based on the total supporting evidence, this alteration is interpreted as a disease-causing mutation, but may represent a low- or lower-penetrance MSH6 allele with regards to CMMR-D. - |
| Likely pathogenic, criteria provided, single submitter | curation | Sema4, Sema4 | Apr 13, 2021 | - - |
Lynch syndrome Pathogenic:2
| Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Oct 14, 2019 | The p.Arg1076Cys variant in MSH6 has been reported in the heterozygous state in at least 12 individuals with Lynch syndrome-associated cancers (Plaschke 2004, Limburg 2011, Liccardo 2017, Rohlin 2017, Rubio 2016, Schultheis 2016, Klarskov 2011, Schofield 2009, Nilbert 2009) and in the homozygous state in 1 individual with relatively late onset colorectal cancer, suggesting that it may be a hypomorphic allele (Gardes 2012). Additionally, the p.Arg1076Cys variant has also been reported in the compound heterozygous state in 5 individuals (from four families) with clinical features of constitutional mismatch repair deficiency (Okkels 2006, Plaschke 2006, Jasperson 2011, Gardes 2012). It has also been identified in 0.03% (5/18386) of East Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). Immunohistochemistry staining of tumor tissue samples in the majority of affected individuals showed loss of MSH6 staining, providing evidence that the Arg1076Cys variant may impact protein function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein. This variant was classified as Likely Pathogenic on March 9, 2018 by the ClinGen-approved InSiGHT expert panel (RCV000074823.4). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP Criteria applied: PM3, PS4_Moderate, PS3_Supporting, PP3, PM2_Supporting. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jan 08, 2024 | This missense variant replaces arginine with cysteine at codon 1076 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 heterozygous state in multiple individuals and families affected with Lynch syndrome-associated cancer (PMID: 18566915, 19072991, 21056691, 22949379, 27696107, 28481244, 30521064). This variant has been reported in at least five individuals found in trans with pathogenic MSH6 co-variants (compound heterozygous) who were affected with early-onset mismatch repair deficient colorectal cancer and/or polyps and some features of constitutional mismatch repair deficiency (CMMR-D) syndrome (PMID: 16418736, 16525781, 18409202, 21039432, 21836479, 22250089, 29785566). This variant was also detected in a homozygous individual affected with recurrent colorectal cancer in his 40s and multiple colorectal adenomas and polyps (PMID: 22250089). This variant has been identified in 24/251346 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. - |
Breast and/or ovarian cancer Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Nov 09, 2022 | - - |
Hereditary nonpolyposis colon cancer Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 03, 2024 | Variant summary: MSH6 c.3226C>T (p.Arg1076Cys) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, core domain (IPR007696) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.5e-05 in 251346 control chromosomes (gnomAD). This frequency is lower than expected for a pathogenic variant in MSH6 causing Lynch Syndrome (9.5e-05 vs 0.00014), allowing no conclusion about variant significance. The variant, c.3226C>T, has been reported in compound heterozygous state with other pathogenic MSH6 truncating variants in several patients with constitutional mismatch repair deficiency (CMMRD) syndrome, i.e. early-onset colorectal cancer, adenomatous polyposis and cafe-au-lait spots (Okkels 2006, Plaschke 2006, Rahner 2008, Allred 2013). In many of these cases the loss of MSH6 staining in both the tumor and normal cells was described, pointing to a bi-allelic MSH6 mutation. The variant was also reported in heterozygosity in individuals affected by Lynch syndrome (Schofield 2009, Lagerstedt-Robinson 2016, Rohlin 2016, Liccardo 2017, Espenschied 2017, Kim_2022, Duzkale_2021), where in several cases the associated tumor demonstrated isolated loss of MSH6 staining. However, within the reported CMMRD families the variant was also observed in heterozygous state in unaffected family members (Plaschke 2006, Okkels 2006, Allred 2013), suggesting its role in causing Lynch syndrome is uncertain. This variant was also found in a homozygote who developed colorectal tumors at the age of 45 and 49 year, together with multiple colon adenomas and polyps (Gardes 2012), a disease history that is closer to Lynch syndrome than CMMRD. However, in LCLs derived from this patient, though MSH6 mRNA was detectable, Western blot analysis demonstrated the lack of MSH6 protein, a finding that is consistent with CMMRD (Gardes 2012). These data indicate that the variant may be a hypomorphic allele, though no functional studies are available to support this assumption. The following publications have been ascertained in the context of this evaluation (PMID: 34637943, 34271781, 28514183, 22250089, 35884469, 21836479, 27601186, 28481244, 21056691, 35725860, 36243179, 16525781, 16418736, 18409202, 27696107, 19072991, 23621914, 22949379, Allred_2013). ClinVar contains an entry for this variant (Variation ID: 89357). Based on the evidence outlined above, the variant was classified as likely pathogenic for constitutional mismatch repair deficiency (CMMRD) syndrome. - |
Gastric cancer Pathogenic:1
| Pathogenic, no assertion criteria provided | research | Laboratory for Genotyping Development, RIKEN | Jul 01, 2021 | - - |
Inherited prostate cancer Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Genomics and Molecular Medicine Service, East Genomic Laboratory Hub, NHS Genomic Medicine Service | May 08, 2024 | PM3_Strong,PP3,PP4_Moderate - |
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1076 of the MSH6 protein (p.Arg1076Cys). This variant is present in population databases (rs63750617, gnomAD 0.03%). This missense change has been observed in individuals with clinical features of Lynch syndrome and also in unaffected individuals (PMID: 21056691, 27696107, 18566915, Invitae, external communication). Also, it has been observed in several individuals with constitutional mismatch repair deficiency (CMMR-D) syndrome. In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant (PMID: 15483016, 16418736, 16525781, 21039432, 18409202). These individuals were affected with early-onset colorectal cancer, glioblastoma, endometrial cancer, adenomatous polyposis, and/or cafe-au-lait spots. However, this variant was also found to be homozygous in individuals with mild CMMR-D features; these individuals were affected with colorectal cancer and kidney cancer (PMID: 22250089, Invitae). ClinVar contains an entry for this variant (Variation ID: 89357). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MSH6 protein function. For these reasons, this variant has been classified as Pathogenic. - |
Breast carcinoma Pathogenic:1
| Likely pathogenic, no assertion criteria provided | clinical testing | Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences | Aug 16, 2021 | Invasive Ductal Carcinoma Estrogen Receptor: Positive Progesterone Receptor: Positive HER2 Receptor: Positive - |
MSH6-related disorder Pathogenic:1
| Likely pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 23, 2024 | The MSH6 c.3226C>T variant is predicted to result in the amino acid substitution p.Arg1076Cys. This variant has been reported in individuals with colorectal, ovarian and endometrial cancer with tumors exhibiting loss of MSH6 protein levels (Plaschke et al. 2004. PubMed ID: 15483016; Limburg et al. 2011. PubMed ID: 21056691; Thompson et al. 2013. PubMed ID: 22949379; Table S1, Carter et al. 2018. PubMed ID: 30322717; eTable 2, Jiang et al. 2019. PubMed ID: 30521064). It has been reported in the compound heterozygous state with other MSH6 pathogenic variants in individuals with early-onset colorectal cancer, and constitutional mismatch repair deficiency (Okkels et al. 2006. PubMed ID: 16525781; Rahner et al. 2008. PubMed ID: 18409202; Jasperson et al. 2011. PubMed ID: 21039432) and has been reported in the homozygous state in an individual with colorectal cancer (AlHarbi et al. 2023. PubMed ID: 37306523). This variant is reported in 0.027% of alleles in East Asian decent in gnomAD and is interpreted as likely pathogenic or pathogenic in ClinVar from multiple laboratories and the International Society for Gastrointestinal Hereditary Tumours (InSiGHT) expert panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/89357/). This variant is interpreted as likely pathogenic. - |
Malignant tumor of breast Pathogenic:1
| Likely pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The MSH6 p.Arg1076Cys variant was identified in 10 of 5256 proband chromosomes (frequency: 0.002) from individuals or families with Lynch syndrome, early onset colorectal cancer, or endometrial cancer (Lagerstedt-Robinson 2016, Liccardo 2017, Limburg 2011, Nilbert 2009, Okkels 2012, Plaschke 2004, Rohlin 2017, Rubio 2016, Schofield 2009). The variant was also identified in dbSNP (ID: rs63750617) as “With Pathogenic, Uncertain significance allele”, ClinVar (classified as likely pathogenic by an InSiGHT expert panel in 2018, Ambry Genetics, GeneDx, and three other submitters; and as pathogenic by Invitae), and UMD-LSDB (3x classified neutral). The variant was identified in multiple cases with co-occurring, pathogenic MSH6 variants in patients with later-onset Lynch Syndrome-related cancers or mild Constitutional Mismatch Repair Deficiency-like phenotypes (Gardes 2012, Jasperson 2011, Okkels 2006, Okkels 2012, Plaschke 2006, Rahner 2007, Thompson 2013) as well as in the homozygous state in a patient with colorectal cancer at ages 45 and 49 (Gardes 2012), suggesting that this could be a hypomorphic variant. In vitro studies showed a normal transcript by RT-PCR RNA analysis, while Western blot analysis did not detect MSH6 protein (Thompson 2013, Gardes 2012).The variant was identified in control databases in 24 of 246118 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 2 of 15304 chromosomes (freq: 0.0001), Latino in 2 of 33554 chromosomes (freq: 0.00006), European in 9 of 111618 chromosomes (freq: 0.00008), Ashkenazi Jewish in 1 of 9846 chromosomes (freq: 0.0001), East Asian in 5 of 17240 chromosomes (freq: 0.0003), and South Asian in 5 of 30780 chromosomes (freq: 0.0002), while it was not observed in the Other or Finnish populations. The p.Arg1076 residue is conserved across mammals and other organisms and 5 of 5 computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time, although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic. - |
Endometrial carcinoma Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 24, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Benign
.;.;T;D;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
.;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
.;.;.;M;.
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
.;D;.;D;D
REVEL
Pathogenic
Sift
Uncertain
.;D;.;D;D
Sift4G
Benign
T;D;T;D;T
Polyphen
0.99
.;.;.;D;.
Vest4
MutPred
0.84
.;.;.;Gain of catalytic residue at M1074 (P = 0.039);.;
MVP
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at