Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000222380 | SCV000278395 | uncertain significance | Hereditary cancer-predisposing syndrome | 2024-09-09 | criteria provided, single submitter | clinical testing | The c.3801+3A>G intronic variant results from an A to G substitution 3 nucleotides after coding exon 8 in the MSH6 gene. This nucleotide position is not well conserved in available vertebrate species. In silico splice site analysis for this alteration is inconclusive; however, direct evidence is insufficient at this time (Ambry internal data). Based on the available evidence, the clinical significance of this variant remains unclear. |
| Sema4, |
RCV000222380 | SCV002528069 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-09-15 | criteria provided, single submitter | curation | |
| Labcorp Genetics |
RCV002519740 | SCV003020595 | likely benign | Hereditary nonpolyposis colorectal neoplasms | 2023-07-10 | criteria provided, single submitter | clinical testing | |
| Color Diagnostics, |
RCV000222380 | SCV004357759 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-10-25 | criteria provided, single submitter | clinical testing | This variant causes an A to G nucleotide substitution at the +3 position of intron 8 of the MSH6 gene. Splice site prediction tools are inconclusive regarding the impact of this variant on RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/251200 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, |
RCV001355239 | SCV001550065 | uncertain significance | Carcinoma of colon | no assertion criteria provided | clinical testing | The MSH6 c.3801+3A>G variant was not identified in the literature nor was it identified in the COGR, UMD-LSDB, Zhejiang University Database, Mismatch Repair Genes Variant Database, or the in Insight Hereditary Tumors database. The variant was identified in dbSNP (ID: rs753049136) as "With Uncertain significance allele", and in ClinVar (classified as uncertain significance by Ambry Genetics). The variant was identified in 1 of 246000 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in European population in 1 of 111520 chromosomes (freq: 0.000009), but not in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The c.3801+3A>G variant is located in the 5' splice region but does not affect the invariant +1 and +2 positions. However, positions +3 to +6 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. In addition, 3 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% 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. |