ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1144C>T (p.His382Tyr) (rs587779207)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000162700 SCV000213155 likely benign Hereditary cancer-predisposing syndrome 2018-11-16 criteria provided, single submitter clinical testing Co-occurence with a mutation in another gene that clearly explains a proband's phenotype;In silico models in agreement (benign)
GeneDx RCV000213163 SCV000279483 uncertain significance not provided 2018-05-29 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.1144C>T at the cDNA level, p.His382Tyr (H382Y) at the protein level, and results in the change of a Histidine to a Tyrosine (CAC>TAC). This variant has been reported in at least one individual with breast cancer (Lu 2015). MSH6 His382Tyr was not observed at a significant allele frequency in large population cohorts (Lek 2016). MSH6 His382Tyr is located in the mismatch binding domain and within the nuclear localization signal (Warren 2007, Gassman 2011, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether MSH6 His382Tyr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl RCV000411429 SCV000489167 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2016-08-29 criteria provided, single submitter clinical testing
Invitae RCV000627690 SCV000551091 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2020-10-21 criteria provided, single submitter clinical testing This sequence change replaces histidine with tyrosine at codon 382 of the MSH6 protein (p.His382Tyr). The histidine residue is weakly conserved and there is a moderate physicochemical difference between histidine and tyrosine. This variant is present in population databases (rs587779207, ExAC <0.01%). This variant has been reported in an individual affected with breast cancer (PMID: 26689913). It has also been reported in an individual affected with colon cancer in the Leiden Open-source Variation Database (PMID: 21520333). However, in that individual, a pathogenic allele was also identified in the MSH2 gene, which suggests that this c.1144C>T variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 89176). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD), and an algorithm developed specifically for the MSH6 gene (PMID: 26333163), suggest that this missense change is likely to be tolerated. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Health, Inc RCV000162700 SCV000690175 uncertain significance Hereditary cancer-predisposing syndrome 2020-10-06 criteria provided, single submitter clinical testing This missense variant replaces histidine with tyrosine at codon 382 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 26689913) and an individual in a cohort that was not selected for cancer phenotype (PMID: 31422574). This variant also has been reported in an individual affected with colorectal cancer (LOVD database; https://databases.lovd.nl/shared/individuals/00187081). This variant has been identified in 6/282326 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 RCV001255541 SCV001432008 uncertain significance not specified 2021-05-19 criteria provided, single submitter clinical testing Variant summary: MSH6 c.1144C>T (p.His382Tyr) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 250932 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1144C>T has been reported in the literature in an individual affected with breast cancer (Lu_2015), however it was also found in an individual in a non-cancer related cohort (Kraemer_2019). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. 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. Four labs classified the variant as VUS whle one classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.

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