ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.2384T>C (p.Ile795Thr) (rs202127474)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001084037 SCV000166220 likely benign Hereditary nonpolyposis colorectal neoplasms 2020-11-16 criteria provided, single submitter clinical testing
GeneDx RCV000588994 SCV000211296 uncertain significance not provided 2018-06-19 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.2384T>C at the cDNA level, p.Ile795Thr (I795T) at the protein level, and results in the change of an Isoleucine to a Threonine (ATA>ACA). Although this variant has not, to our knowledge, been published in the literature as a germline variant, MSH6 Ile795Thr has been reported as a somatic variant in a microsatellite stable serous endometrial tumor (Le Gallo 2012, Price 2013). MSH6 Ile795Thr was observed with an allele frequency of 0.19% (57/30782) in individuals of South Asian ancestry in large population cohorts (Lek 2016). This variant is located in the Lever domain (Warren 2007, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MSH6 Ile795Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000160681 SCV000214998 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-31 criteria provided, single submitter clinical testing The p.I795T variant (also known as c.2384T>C), located in coding exon 4 of the MSH6 gene, results from a T to C substitution at nucleotide position 2384. The isoleucine at codon 795 is replaced by threonine, an amino acid with similar properties. This alteration was previously identified in an individual with microsatellite stable serous endometrial cancer (Le Gallo M et al. Nat. Genet. 2012 Dec;44:1310-5; Price JC et al. PLoS ONE. 2014;8:e63313). 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.
Pathway Genomics RCV000172814 SCV000223780 uncertain significance Lynch syndrome I 2014-10-30 criteria provided, single submitter clinical testing
Counsyl RCV000412250 SCV000488581 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2016-05-03 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000588994 SCV000601530 likely benign not provided 2019-12-06 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000588994 SCV000695811 uncertain significance not provided 2016-07-11 criteria provided, single submitter clinical testing variant summary: The MSH6 c.2384T>C (p.Ile795Thr) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect multiple ESE sites. However, these predictions have yet to be confirmed by functional studies. This variant was found in 38/121196 control chromosomes, predominantly observed in the South Asian subpopulation at a frequency of 0.0020604 (34/16502). This frequency is about 15 times the estimated maximal expected allele frequency of a pathogenic MSH6 variant (0.0001421), suggesting this is likely a benign polymorphism found primarily in the populations of South Asian origin. This variant also has been reported in one serous endometrial tumor sample with stable microsatellite markers. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS-possibly benign.
Color Health, Inc RCV000160681 SCV000902755 likely benign Hereditary cancer-predisposing syndrome 2017-06-22 criteria provided, single submitter clinical testing

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