Submissions for variant NM_000179.3(MSH6):c.3986C>T (p.Ser1329Leu)

gnomAD frequency: 0.00006  dbSNP: rs199594809

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000074965	SCV000108180	likely benign	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Multifactorial likelihood analysis posterior probability 0.001-0.049
GeneDx	RCV001311190	SCV000149338	likely benign	not provided	2020-01-17	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 22290698, 18301448, 23621914, 25142776, 27060149, 17531815)
Ambry Genetics	RCV000115429	SCV000186415	likely benign	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000524202	SCV000254323	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-26	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212693	SCV000601595	uncertain significance	not specified	2016-09-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000212693	SCV000695905	uncertain significance	not specified	2019-05-07	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.3986C>T (p.Ser1329Leu) results in a non-conservative amino acid change located in the C-terminal domain (IPR000432) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. In addition, two in silico studies predicted the variant being benign/neutral (Terui_2013, Ali_2012). The variant allele was found at a frequency of 4.5e-05 in 246306 control chromosomes, predominantly at a frequency of 9.9e-05 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in MSH6 causing Lynch Syndrome (4.5e-05 vs 0.00014), allowing no conclusion about variant significance. The variant, c.3986C>T, has been reported in the literature in individuals affected with colorectal cancer (Steinke_2008, Kraus_2014, Graham_2015) who displayed normal IHC staining patterns, had microsatellite stable (MSS) analysis and/or did not fulfill the classical diagnostic criteria for Lynch syndrome (example, the revised Bethesda criteria, Kraus_2014 and Steinke_2008). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS (n=3), likely benign (n=2)). An expert panel (InSIGHT) has submitted a classification for this variant in ClinVar before 2014 (in 2013) as likely benign citing a multifactorial likelihood analysis posterior probability 0.001-0.049. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Color Diagnostics, LLC DBA Color Health	RCV000115429	SCV000902787	likely benign	Hereditary cancer-predisposing syndrome	2015-11-17	criteria provided, single submitter	clinical testing
Mendelics	RCV000986743	SCV001135855	benign	Lynch syndrome 5	2023-08-22	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000986743	SCV001300824	uncertain significance	Lynch syndrome 5	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000986743	SCV001429598	uncertain significance	Lynch syndrome 5	2018-06-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001311190	SCV001501273	likely benign	not provided	2024-06-01	criteria provided, single submitter	clinical testing	MSH6: BS3:Supporting
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV001311190	SCV002010081	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115429	SCV002536309	likely benign	Hereditary cancer-predisposing syndrome	2021-05-05	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000212693	SCV002552371	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004537282	SCV004746790	uncertain significance	MSH6-related disorder	2023-10-24	no assertion criteria provided	clinical testing	The MSH6 c.3986C>T variant is predicted to result in the amino acid substitution p.Ser1329Leu. This variant was reported in individuals with Lynch syndrome (Steinke et al. 2008. PubMed ID: 18301448, Supplementary table 1; Kraus et al 2014. PubMed ID: 25142776; Graham et al. 2015. PubMed ID: 26099011). Prediction models, however, indicate that this missense change is likely to be tolerated (Ali et al. 2012. PubMed ID: 22290698; Terui et al. 2013. PubMed ID: 23621914). Nevertheless, such prediction models have not been confirmed with functional studies. Additionally, this variant was reported in a patient who also harbored a known pathogenic BRCA1 variant (Nikitin et al. 2020. PubMed ID: 32547938, Supplementary Table 2). A large clinical database also documents this variant with conflicting interpretations of pathogenicity (https://www.ncbi.nlm.nih.gov/clinvar/variation/89497/). This variant is reported in 0.010% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-48033775-C-T). Although we suspect this variant may be benign, at this time the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.