ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.2827G>T (p.Asp943Tyr) (rs143520357)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131640 SCV000186664 likely benign Hereditary cancer-predisposing syndrome 2019-08-15 criteria provided, single submitter clinical testing Rare (0.1%) in general population databases (dbsnp, esp, 1000 genomes) ;In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Other data supporting benign classification;Other strong data supporting benign classification
GeneDx RCV000212672 SCV000211303 uncertain significance not provided 2016-11-18 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.2827G>T at the cDNA level, p.Asp943Tyr (D943Y) at the protein level, and results in the change of an Aspartic Acid to a Tyrosine (GAC>TAC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Asp943Tyr was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Aspartic Acid and Tyrosine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Asp943Tyr occurs at a position that is conserved through mammals and is located within the MutS domain IV (Terui 2013). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether MSH6 Asp943Tyr is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000205918 SCV000261184 uncertain significance Hereditary nonpolyposis colon cancer 2019-12-19 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with tyrosine at codon 943 of the MSH6 protein (p.Asp943Tyr). The aspartic acid residue is highly conserved and there is a large physicochemical difference between aspartic acid and tyrosine. This variant is present in population databases (rs143520357, ExAC 0.006%). This variant has been reported in individuals affected with breast cancer (PMID: 25186627) and pancreatic cancer (PMID: 25479140). ClinVar contains an entry for this variant (Variation ID: 142495). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). However, an algorithm developed specifically for the MSH6 protein suggests that this missense change is likely to be deleterious (PMID: 23621914). CN517202 of these predictions have been confirmed by published functional studies. 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.
Counsyl RCV000412088 SCV000489142 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2016-08-23 criteria provided, single submitter clinical testing
Color RCV000131640 SCV000537570 uncertain significance Hereditary cancer-predisposing syndrome 2019-09-24 criteria provided, single submitter clinical testing

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