Submissions for variant NM_000179.3(MSH6):c.2342C>T (p.Pro781Leu)

dbSNP: rs1553413710

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589271	SCV000695808	uncertain significance	not provided	2017-03-03	criteria provided, single submitter	clinical testing	Variant summary: The MSH6 c.2342C>T (p.Pro781Leu) variant involves the alteration of a conserved nucleotide, resulting in a missense substitution. The variant is found within the functional core domain of the protein (InterPro) and 4/4 in silico tools predict a damaging outcome (SNPs&GO not captured due to low reliability index). This variant is absent from the large control population database ExAC (0/121254 control chromosomes). To our knowledge, the variant of interest has not been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000664307	SCV000788239	pathogenic	Lynch syndrome	2018-04-01	criteria provided, single submitter	research	The MSH6 gene variant designated as NM_000179.2:c.2342C>T (p.Pro781Leu) is classified as pathogenic. Cosegregation analysis of one observed family was performed using analyze.myvariant.org (Rañola et al, 2018, PMID:28965303) and shows a likelihood ratio of 1.22 to 1, providing some evidence for pathogenicity (Thompson et al., 2003, PMID:2900794). Using computer predictions from MAPP and Polyphen2 algorithms we estimated a pretest probability of 90% supporting pathogenicity (Thompson et al, 2013, PMID:22949379). Combining pretest probability and segregation likelihood gives 92% probability of pathogenicity. In addition, this patient’s tumor had microsatellite instability and loss of MSH6, providing further evidence for pathogenicity. Bayesian analysis integrating all data (Tavtigian et al, 2018, PMID:29300386) gives over 99% probability of pathogenicity, which is consistent with a classification of pathogenic. This variant is predicted to alter MSH6 function and cause Lynch syndrome-associated cancers. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study.
Invitae	RCV002527180	SCV003019719	likely pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-12-30	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 781 of the MSH6 protein (p.Pro781Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Lynch syndrome (PMID: 30374176; Invitae). ClinVar contains an entry for this variant (Variation ID: 433914). 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) performed at Invitae indicates that this missense variant is expected to disrupt MSH6 protein function with a positive predictive value of 95%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics	RCV004023356	SCV005032832	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-01-17	criteria provided, single submitter	clinical testing	The p.P781L variant (also known as c.2342C>T), located in coding exon 4 of the MSH6 gene, results from a C to T substitution at nucleotide position 2342. The proline at codon 781 is replaced by leucine, an amino acid with similar properties. This alteration was detected in a proband whose tumor showed high microsatellite instability (MSI-H) and loss of MSH6 by immunohistochemistry (IHC), and was classified as pathogenic by a study that evaluated multiple lines of evidence, including population data, functional evidence, in silico prediction models, segregation with disease and clinical phenotype including tumor characteristics (Tsai GJ et al. Genet Med, 2019 Jun;21:1435-1442). Another alteration at the same codon, p.P781S (c.2341C>T), has been identified in multiple individuals whose tumors were MSI-H and demonstrated loss of MSH6 protein expression by IHC (Buchanan DD et al. J. Gastroenterol. Hepatol., 2017 Feb;32:427-438; Ambry internal data). 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000589271	SCV000592606	uncertain significance	not provided		no assertion criteria provided	clinical testing	The Pro781Leu Variant has not been previously detected in the literature nor by our laboratory. The Pro781 residue is conserved in mammals and lower species and computational analyses (PolyPhen-2, AlignGVGD) suggest that the Pro781Leu variant may impact the protein. However, this information is not predictive enough to assume pathogenicity. It should be noted that this lab has only sequenced the MSH6 gene in 126 individuals such that the full spectrum of benign variation has not yet been defined for this gene, increasing the possibility that this may be a benign variant. In summary, based on the above information, the clinical significance of this variant cannot be determined at this time.