ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1386+1G>A (rs267607957)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000076137 SCV000592500 pathogenic Lynch syndrome no assertion criteria provided clinical testing The c.1386+1G>A variant was identified in 3 of 3562 proband chromosomes (frequency: 0.001) from individuals or families with Lynch Syndrome (Auclair, 2006; Mangold, 2005). The variant was also identified in dbSNP (ID: rs267607957) “With pathogenic allele”, HGMD, “MMR Gene Unclassified Variants Database”, “InSiGHT Colon Cancer Database” (as likely pathogenic), and the ClinVar database. The c.1386+1G>A variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the invariant region of the splice consensus sequence. Studies by Auclair and Betz have shown this variant to cause the loss of exon 8 and Mueller-Koch links this loss to a loss of expression of the MSH2 protein in colon tumours. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing in 4 of 5 programs. Loss of function variants of the MSH2 gene are an established mechanism of disease in Lynch syndrome and this is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.

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