ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.2249C>A (p.Thr750Lys) (rs730881817)

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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 RCV000491170 SCV000580271 likely benign Hereditary cancer-predisposing syndrome 2016-06-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Seen in trans with a mutation or in homozygous state in individual without severe disease for that gene
Color RCV000491170 SCV000685269 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-15 criteria provided, single submitter clinical testing
Counsyl RCV000663327 SCV000786599 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2018-06-05 criteria provided, single submitter clinical testing
GeneDx RCV000587383 SCV000211350 uncertain significance not provided 2015-07-28 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.2249C>A at the cDNA level, p.Thr750Lys (T750K) at the protein level, and results in the change of a Threonine to a Lysine (ACA>AAA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Thr750Lys was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Threonine and Lysine differ in some properties, this is considered a semi-conservative amino acid substitution. MSH6 Thr750Lys occurs at a position that is conserved through mammals and is located in domain III of the MutS domain (Terui 2013). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether MSH6 Thr750Lys is pathogenic or benign. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000587383 SCV000695804 uncertain significance not provided 2016-01-04 criteria provided, single submitter clinical testing
Invitae RCV000205769 SCV000261416 uncertain significance Hereditary nonpolyposis colon cancer 2018-09-04 criteria provided, single submitter clinical testing This sequence change replaces threonine with lysine at codon 750 of the MSH6 protein (p.Thr750Lys). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and lysine. This variant is present in population databases (rs730881817, ExAC 0.002%). This variant has not been reported in the literature in individuals with a MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 182660). 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant has uncertain impact on MSH6 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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