Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV002322645 | SCV002610027 | pathogenic | Hereditary cancer-predisposing syndrome | 2020-04-22 | criteria provided, single submitter | clinical testing | The c.3172+2delT intronic pathogenic mutation, located in intron 4 of the MSH6 gene, results from a deletion of one nucleotide within intron 4 of the MSH6 gene. This variant has been identified in a proband(s) whose Lynch syndrome-associated tumor demonstrated loss of MSH6 expression by immunohistochemistry (IHC) (Ambry internal data). This variant has also been identified as somatic in conjunction with a somatic pathogenic MSH6 variant in an endometrial tumor that demonstrated high microsatellite instability with loss of MSH6 expression by 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; however, direct evidence is insufficient at this time (Ambry internal data). Another alteration impacting the same donor site (c.3172+1G>T) has been detected in an individual who met Amsterdam I/II criteria for Lynch syndrome and their tumor demonstrated loss of MSH6 expression by IHC, and in several individuals whose Lynch syndrome-associated tumors demonstrated loss of MSH6 expression by IHC (Talseth-Palmer BA et al. Hered. Cancer Clin. Pract. 2010 May;8:5; Ambry internal data). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. |