Submissions for variant NM_000179.3(MSH6):c.1106C>T (p.Thr369Ile)

gnomAD frequency: 0.00001  dbSNP: rs375974046

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212645	SCV000149277	uncertain significance	not provided	2023-10-05	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with microsatellite-stable endometrial cancer, colorectal cancer, ovarian cancer and/or colon polyps, and also present in unaffected control(s) (Price et al., 2014; Shirts et al., 2016; Rosenthal et al., 2018); This variant is associated with the following publications: (PMID: 23621914, 26845104, 23755103, 33471991, 30267214, 17531815, 21120944)
Ambry Genetics	RCV000115368	SCV000216876	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-17	criteria provided, single submitter	clinical testing	The p.T369I variant (also known as c.1106C>T), located in coding exon 4 of the MSH6 gene, results from a C to T substitution at nucleotide position 1106. The threonine at codon 369 is replaced by isoleucine, an amino acid with similar properties. This alteration has been reported in a 55-year-old proband with ovarian cancer ascertained via multigene panel testing (Shirts B et al. Genet. Med. 2016 10;18(10):974-81). In another study, this variant was detected in 0/165 colorectal cancer and/or polyposis patients and was identified in 1/2512 control individuals from a healthy population database (Rosenthal EA et al. Hum Genet, 2018 Oct;137:795-806). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000210148	SCV000266199	uncertain significance	Lynch syndrome	2015-11-20	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000528613	SCV000624612	likely benign	Hereditary nonpolyposis colorectal neoplasms	2023-11-29	criteria provided, single submitter	clinical testing
Counsyl	RCV000662663	SCV000785352	uncertain significance	Lynch syndrome 5	2017-07-11	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115368	SCV001344147	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-06	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with isoleucine at codon 369 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with ovarian cancer (PMID: 26845104), or colonic polyposis (Short 2018 , dissertation, Cardiff University). This variant has been identified in 4/250994 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193101	SCV001361709	uncertain significance	not specified	2019-03-07	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.1106C>T (p.Thr369Ile) results in a non-conservative amino acid change in 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 1.6e-05 in 245742 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. This variant has been reported in the literature in one individual affected with ovarian cancer (Shirts_2016). The report does 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. Six ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Sema4, Sema4	RCV000115368	SCV002535591	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-11	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000662663	SCV004018956	likely benign	Lynch syndrome 5	2023-03-29	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
All of Us Research Program, National Institutes of Health	RCV000210148	SCV004842936	uncertain significance	Lynch syndrome	2023-12-18	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with isoleucine at codon 369 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with ovarian cancer (PMID: 26845104), or colonic polyposis (Short 2018 , dissertation, Cardiff University). This variant has been identified in 4/250994 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Baylor Genetics	RCV004566999	SCV005055974	uncertain significance	Endometrial carcinoma	2023-11-17	criteria provided, single submitter	clinical testing
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000415687	SCV000493756	uncertain significance	Lynch syndrome 1	2015-12-04	no assertion criteria provided	clinical testing