ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3226C>T (p.Arg1076Cys) (rs63750617)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000074823 SCV000108034 likely pathogenic Lynch syndrome I 2018-03-09 reviewed by expert panel curation 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
Ambry Genetics RCV000162445 SCV000212797 likely pathogenic Hereditary cancer-predisposing syndrome 2019-08-30 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Other data supporting pathogenic classification
Invitae RCV000524159 SCV000283794 pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-12-29 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 1076 of the MSH6 protein (p.Arg1076Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs63750617, ExAC 0.03%). This variant has been reported in individuals with colon cancer (PMID: 21056691, 27696107) and in two families from the Danish HNPCC register (PMID: 18566915). ClinVar contains an entry for this variant (Variation ID: 89357). In several unrelated individuals with constitutional mismatch repair deficiency (CMMR-D) syndrome, this p.Arg1076Cys missense variant was found in trans with different pathogenic MSH6 truncating variants (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. An individual homozygous for this variant did not present with CMMR-D, but did develop colorectal tumors at 45 and 49 years old (PMID: 22250089). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000254700 SCV000321908 likely pathogenic not provided 2019-01-15 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.3226C>T at the cDNA level, p.Arg1076Cys (R1076C) at the protein level, and results in the change of an Arginine to a Cysteine (CGC>TGC). This variant has been observed in individuals with a personal and/or family history of colorectal cancer (Nilbert 2009, Liccardo 2017, Rohlin 2017) as well as at least three individuals with colorectal cancer and one with synchronous endometrial and ovarian cancers, with most tumors demonstrating loss of MSH6 protein expression (Schofield 2009, Limburg 2011, Schultheis 2016, Rubio 2016). In addition, this variant has been observed in the compound heterozygous state with a truncating MSH6 variant in five individuals from four families with histories suggestive of constitutional mismatch repair deficiency syndrome, with absent MSH6 expression in both tumor and normal tissue from most individuals (Plaschke 2006, Okkels 2006, Rahner 2008, Jasperson 2011, Bush 2018). This variant 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 (Gardes 2012, Okkels 2006, Rahner 2008). MSH6 Arg1076Cys was observed at an allele frequency of 0.03% (5/17,240) in individuals of East Asian ancestry in large population cohorts (Lek 2016). MSH6 Arg1076Cys is located in the Lever domain (Warren 2007, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on the currently available evidence, we consider MSH6 Arg1076Cys to be a likely pathogenic variant.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000254700 SCV000601562 likely pathogenic not provided 2018-01-18 criteria provided, single submitter clinical testing
Color RCV000162445 SCV000690333 likely pathogenic Hereditary cancer-predisposing syndrome 2020-02-19 criteria provided, single submitter clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000709742 SCV000840015 likely pathogenic Hereditary nonpolyposis colorectal cancer type 5 2017-10-15 criteria provided, single submitter clinical testing 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.
Integrated Genetics/Laboratory Corporation of America RCV000780464 SCV000917733 likely pathogenic Lynch syndrome 2018-09-06 criteria provided, single submitter clinical testing 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 9.8e-05 in 246118 control chromosomes (gnomAD). This frequency is lower than expected for a pathogenic variant in MSH6 causing Lynch Syndrome (9.8e-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), 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. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (1x) / likely pathogenic (5x). ACMG recommends reporting incidental findings (mutations that cause or are likely to cause other phenotypes than those indicated for testing, i.e. Lynch Syndrome here) in this gene. Based on the evidence outlined above, the variant was classified as likely pathogenic for constitutional mismatch repair deficiency (CMMRD) syndrome.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000709742 SCV000993566 likely pathogenic Hereditary nonpolyposis colorectal cancer type 5 2018-09-11 criteria provided, single submitter research
Mendelics RCV000709742 SCV001135834 likely pathogenic Hereditary nonpolyposis colorectal cancer type 5 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000254700 SCV001152299 likely pathogenic not provided 2018-09-01 criteria provided, single submitter clinical testing

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