Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV001020791 | SCV001182317 | pathogenic | Hereditary cancer-predisposing syndrome | 2021-04-30 | criteria provided, single submitter | clinical testing | The c.3646+2_3646+3insCT intronic pathogenic mutation results from an insertion of two nucleotides (CT) between nucleotide positions 3646+2 and 3646+3 after exon 7 of the MSH6 gene. This variant was identified in a proband whose Lynch syndrome-associated tumor demonstrated high microsatellite instability (MSI-H) and isolated loss of MSH6 on immunohistochemistry (IHC) (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
All of Us Research Program, |
RCV004004606 | SCV004835455 | likely pathogenic | Lynch syndrome | 2023-11-20 | criteria provided, single submitter | clinical testing | This variant causes an insertion of two nucleotides between +2 and +3 position in intron 7 of the MSH6 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. This variant has been reported in an individual affected with Lynch syndrome (ClinVar: SCV001182317.3). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same splice donor site, c.3646+2T>C, is known to be disease-causing (ClinVar variation ID: 455274). Loss of MSH6 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Likely Pathogenic. |