Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000459417 | SCV000551291 | benign | Hereditary nonpolyposis colorectal neoplasms | 2024-01-15 | criteria provided, single submitter | clinical testing | |
| Gene |
RCV000479642 | SCV000571275 | uncertain significance | not provided | 2022-09-02 | criteria provided, single submitter | clinical testing | In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 21437237) |
| Ambry Genetics | RCV000562409 | SCV000662479 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-08-25 | criteria provided, single submitter | clinical testing | The p.S346C variant (also known as c.1037C>G), located in coding exon 4 of the MSH6 gene, results from a C to G substitution at nucleotide position 1037. The serine at codon 346 is replaced by cysteine, an amino acid with dissimilar 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. |
| Color Diagnostics, |
RCV000562409 | SCV000908367 | uncertain significance | Hereditary cancer-predisposing syndrome | 2018-11-19 | criteria provided, single submitter | clinical testing | |
| Department of Pathology and Laboratory Medicine, |
RCV001357378 | SCV001552835 | uncertain significance | Malignant tumor of breast | no assertion criteria provided | clinical testing | The MSH6 p.Ser346Cys variant was not identified in the literature nor was it identified in the following databases: COGR, COSMIC, MutDB, UMD-LSDB, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, or Insight Hereditary Tumors databases. The variant was identified in dbSNP (ID: rs567785169) as “With Uncertain significance allele”, and in the ClinVar and Clinvitae databases (2x classified as uncertain significance by Invitae and GeneDx). The variant was identified in control databases in 1 of 246056 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). It was observed in the following population: East Asian in 1 of 17248 chromosomes (freq: 0.000058); it was not observed in the African, “Other”, Latino, European Non-Finnish, Ashkenazi Jewish, European Finnish, and South Asian populations. The p.Ser346Cys residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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. |