Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000130615 | SCV000185491 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-09-28 | criteria provided, single submitter | clinical testing | The p.T336S variant (also known as c.1007C>G), located in coding exon 4 of the MSH6 gene, results from a C to G substitution at nucleotide position 1007. The threonine at codon 336 is replaced by serine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Invitae | RCV001219936 | SCV001391903 | likely benign | Hereditary nonpolyposis colorectal neoplasms | 2024-01-14 | criteria provided, single submitter | clinical testing | |
| All of Us Research Program, |
RCV003998069 | SCV004829480 | uncertain significance | Lynch syndrome | 2023-05-16 | criteria provided, single submitter | clinical testing | This missense variant replaces threonine with serine at codon 336 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 not been reported in individuals affected with MSH6-related disorders in the literature. This variant has been identified in 2/251354 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. |
| Department of Pathology and Laboratory Medicine, |
RCV001356288 | SCV001551415 | uncertain significance | not provided | no assertion criteria provided | clinical testing | The MSH6 p.Thr336Ser variant was not identified in the literature nor was it identified in the COGR, Cosmic, MutDB, UMD-LSDB, Zhejiang University Database, Mismatch Repair Genes Variant Database, or Insight Hereditary Tumors databases. The variant was identified in dbSNP (ID: rs587782102) as "With Uncertain significance allele", and in ClinVar database (classified as uncertain significance by Ambry Genetics). The variant was identified in control databases in 2 of 246140 chromosomes at a frequency of 0.000008 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 1 of 111612 chromosomes (freq: 0.000009), and South Asian in 1 of 30782 chromosomes (freq: 0.00003), but not in the African, Other, Latino, Ashkenazi Jewish, East Asian, or Finnish populations. The p.Thr336 residue is conserved in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. |