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 2019-11-05 criteria provided, single submitter clinical testing In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Well-characterized mutation at same position;Rarity in general population databases (dbsnp, esp, 1000 genomes)
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.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000500646 SCV000592582 likely pathogenic Lynch syndrome 2014-05-14 criteria provided, single submitter clinical testing
Invitae RCV000553513 SCV000624635 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-10-21 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 RCV000162486 SCV000690193 likely pathogenic Hereditary cancer-predisposing syndrome 2019-04-05 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America 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 2018-11-24 criteria provided, single submitter clinical testing Not found in the total gnomAD dataset, and the data are high quality. Statistically enriched in patients compared to ethnically matched controls. Predicted to have a damaging effect on the protein. Located in potentially important domain of the protein. One other pathogenic or likely pathogenic variant affects the same amino acid .
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000582500 SCV000691924 uncertain significance not specified no assertion criteria provided clinical testing

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