ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1295T>C (p.Phe432Ser) (rs750528093)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000162486 SCV000212859 likely pathogenic Hereditary cancer-predisposing syndrome 2020-07-30 criteria provided, single submitter clinical testing The p.F432S variant (also known as c.1295T>C), located in coding exon 4 of the MSH6 gene, results from a T to C substitution at nucleotide position 1295. The phenylalanine at codon 432 is replaced by serine, an amino acid with highly dissimilar properties. This alteration has been observed in families that meet Amsterdam criteria and in an individual with clinical features consistent with constitutional mismatch repair deficiency syndrome (CMMRD) (Ambry internal data). This alteration was reported in an individual diagnosed with endometrial cancer whose tumor demonstrated low microsatellite instability and normal MSH6 expression on immunohistochemistry (IHC) (Batte BA et al. Gynecol. Oncol., 2014 Aug;134:319-25; Borras E et al. Cancer Prev Res (Phila), 2017 Oct;10:580-587). This alteration has been reported as functionally defective based on results from a complementation assay performed in mammalian cells (Drost M et al. Genet. Med., 2020 May;22:847-856). Another alteration at the same codon, p.F432A, was shown to have reduced DNA binding and abolished mismatch repair activity in an in vitro functional assay (Dufner P et al. J. Biol. Chem., 2000 Nov;275:36550-5). Based on internal structural analysis using published crystal structures, this alteration is important to protein function and moderately destabilizing to the local structure (Warren JJ et al. Mol. Cell, 2007 May;26:579-92; Sharma M et al. Biophys. J., 2014 Jun;106:2483-92; Reyes GX et al. Chromosoma, 2015 Dec;124:443-62). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
GeneDx RCV000479506 SCV000566575 likely pathogenic not provided 2019-01-17 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.1295T>C at the cDNA level, p.Phe432Ser (F432S) at the protein level, and results in the change of a Phenylalanine to a Serine (TTT>TCT). This variant has been identified in at least one woman with endometrioid endometrial cancer, and a family history of colorectal and/or endometrial cancer, whose tumor displayed presence of MLH1, MSH2, MSH6, and PMS2 by immunohistochemistry and low levels of microsatellite instability (MSI-L) (Batte 2014). In addition, Dufner et al. (2000) performed in vitro functional studies on an alternate variant at the same residue, Phe432Ala, which exhibited that this variant was unable to form stable complexes, abolished DNA-binding, induced ATP hydrolysis and abolished mismatch repair activity. MSH6 Phe432Ser was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Phenylalanine and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Phe432Ser occurs at a position that is conserved across species and is located in domain I of the MutS domain and in the MSH2 binding sites (Kariola 2002, Terui 2013). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the currently available evidence, we consider MSH6 Phe432Ser to be a likely pathogenic variant.
Invitae RCV000553513 SCV000624635 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2020-06-23 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with serine at codon 432 of the MSH6 protein (p.Phe432Ser). The phenylalanine residue is highly conserved and there is a large physicochemical difference between phenylalanine and serine. This variant is not present in population databases (rs750528093, ExAC no frequency). This variant has been observed in an individual affected with endometrial cancer (PMID: 24933100). It has also been observed in individuals affected with Lynch syndrome (PMID: 28765196), and it segregated with disease in a family affected with colon and uterine cancers (Invitae). ClinVar contains an entry for this variant (Variation ID: 183760). Experimental studies have shown that a different variant at this position (p.Phe432Ser) disrupts MSH6 protein function in vitro (PMID: 10938287). This suggests that the phenylalanine residue is critical for MSH6 protein function and that other missense substitutions at this position may also be disruptive, but experiments have not been done to test this possibility. 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. In summary, this variant is a rare missense change that has been observed in multiple affected individuals and segregated with disease in one family. This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Color Health, Inc RCV000162486 SCV000690193 likely pathogenic Hereditary cancer-predisposing syndrome 2021-02-17 criteria provided, single submitter clinical testing This missense variant replaces phenylalanine with serine at codon 432 of the MSH6 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). This substitution disrupts a conserved Phe-X-Glu motif that contacts mispaired DNA bases (PMID: 17531815). A functional study has shown that this variant impacts MMR function in vitro and the equivalent variant in the mouse Msh6 homolog also disrupts DNA mismatch binding and Msh6 function in a genetic screen for tolerance to 6-thioguanine (PMID: 31965077). This variant has been observed in individuals affected with Lynch syndrome-associated cancer (PMID: 24933100, 28765196). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000582500 SCV000919742 uncertain significance not specified 2019-11-20 criteria provided, single submitter clinical testing Variant summary: MSH6 c.1295T>C (p.Phe432Ser) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS-like, N-terminal domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251280 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1295T>C has been reported in the literature in individuals affected with suspected Lynch Syndrome-related endometrial and colorectal cancers (Batte_2014, Borras_2017). A co-occurrence with another likely pathogenic variant has been reported (MLH1 c.1517T>C, p.Val506Ala)(Borras_2017). These reports, however, lack strong evidence for causality (such as cosegregation studies), and therefore do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. One ClinVar entry reports that the variant segregated with disease in a family affected with colorectal and uterine cancers (internal data cited in variant summary submitted to ClinVar on 10/05/17). To our knowledge, no experimental evidence demonstrating an impact on protein function for this specific variant has been reported. However, another variant affecting the same codon, Phe432Ala, has been shown through in-vitro studies to disrupt MSH6 protein activity (Drotschmann_2001, Dufner_2000), suggesting that the Phe432 residue is critical for protein function. Four 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 likely pathogenic using the same evidence utilized in the context of this evaluation. Based on the evidence outlined above, until additional clinical and functional evidence supporting a pathogenic outcome is obtained, we retain the classification of this variant as a VUS-possibly pathogenic
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000479506 SCV001134392 likely pathogenic not provided 2019-10-11 criteria provided, single submitter clinical testing Not found in the total gnomAD dataset. This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls. Predicted to have a damaging effect on the protein. Located in potentially critical domain of the protein. One other pathogenic or likely pathogenic variant affects the same amino acid.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000500646 SCV000592582 likely pathogenic Endometrial carcinoma no assertion criteria provided clinical testing The MSH6 p.Phe432Ser variant was not identified in the literature, nor was it identified in the dbSNP, NHLBI Exome Sequencing Project (Exome Variant Server), HGMD, COSMIC, MutDB, “Mismatch Repair Genes Variant Database”, “MMR Gene Unclassified Variants Database”, “InSiGHT Colon Cancer Database”, “Zhejiang Colon Cancer Database”, ClinVar database, or UMD. The p.Phe432 residue is conserved across mammals and computational analyses (PolyPhen, SIFT, AlignGVGD, BLOSUM) suggest that the p.Phe432Ser variant may impact the protein. However, this information is not predictive enough to assume pathogenicity. Functional studies using site-directed mutagenesis have shown that a different alteration at this position, a substitution of phenylalanine for alanine at residue 432, abolished not only mismatch recognition but also the binding of the MSH2-MSH6 complex to DNA in general (Drotschmann 2001, Dufner 2000, Dalhus 2009), increasing the likelihood that the mutations at this highly conserved residue are of clinical significance. 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 predicted pathogenic.
Mayo Clinic Laboratories, Mayo Clinic RCV000582500 SCV000691924 uncertain significance not specified no assertion criteria provided clinical testing

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