Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| International Society for Gastrointestinal Hereditary Tumours |
RCV000076137 | SCV000107152 | likely pathogenic | Lynch syndrome | 2019-06-21 | reviewed by expert panel | curation | Interrupts canonical donor splice site |
| Invitae | RCV000684786 | SCV000253799 | pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2019-11-13 | criteria provided, single submitter | clinical testing | This sequence change affects a donor splice site in intron 8 of the MSH2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. Loss-of-function variants in MSH2 are known to be pathogenic. This particular variant has been reported in the literature in two individuals affected with Lynch syndrome (PMID: 15849733). Experimental studies have shown that this variant leads to exclusion of exon 8 from the MSH2 transcript (PMID: 16395668, 19669161). For these reasons, this variant has been classified as Pathogenic. |
| Ambry Genetics | RCV000491969 | SCV000580476 | pathogenic | Hereditary cancer-predisposing syndrome | 2018-10-03 | criteria provided, single submitter | clinical testing | The c.1386+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 8 of the MSH2 gene. This mutation has been previously identified in individuals with personal and/or family histories suggestive of HNPCC (Mangold E et al. Int. J. Cancer 2005 Sep;116:692-702; Mueller-Koch Y et al. Gut 2005 Dec;54:1733-40). This mutation was also seen in conjunction with another MSH2 mutation in an MSH2/MSH6 deficient endometrial tumor from a patient who tested negative for germline MSH2 mutations (Watkins JC et al. Int. J. Gynecol. Pathol. 2017 Mar;36:115-127). Additionally, functional analysis has demonstrated that this alteration leads to the skipping of coding exon 8 (Auclair J et al. Hum. Mutat. 2006 Feb;27:145-54; Betz B et al. J. Cancer Res. Clin. Oncol. 2010 Jan;136:123-34). In addition to the clinical data presented in the literature, 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. |
| Department of Pathology and Laboratory Medicine, |
RCV000076137 | SCV000592500 | pathogenic | Lynch syndrome | 2014-08-26 | criteria provided, single submitter | clinical testing | |
| Integrated Genetics/Laboratory Corporation of America | RCV001268971 | SCV000696210 | pathogenic | Hereditary nonpolyposis colon cancer | 2020-11-12 | criteria provided, single submitter | clinical testing | Variant summary: MSH2 c.1386+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: four predict the variant abolishes a 5' splicing donor site. Publications reported experimental evidence, demonstrating that the variant resulted in the skipping of exon 8 (Auclair_2006, Betz_2010). The variant was absent in 248984 control chromosomes (gnomAD). c.1386+1G>A has been reported in the literature in multiple individuals affected with Hereditary Nonpolyposis Colorectal Cancer (e.g. Auclair_2006, Mangold_2005, Mueller-Koch_2005, Betz_2010, Baert-Desurmont_2018, Jiang_2019). These data indicate that the variant is likely to be associated with disease. Three other submitters, including an expert panel (InSiGHT), have provided clinical-significance assessments for this variant in ClinVar after 2014, and classified the variant as pathogenic (2x) / likely pathogenic (1x). Based on the evidence outlined above, the variant was classified as pathogenic. |