ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.3724_3726del (rs63749942)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000074918 SCV000108130 likely pathogenic Lynch syndrome 2019-06-21 reviewed by expert panel curation Multifactorial likelihood analysis posterior probability 0.95-0.99
Ambry Genetics RCV000129144 SCV000183865 likely pathogenic Hereditary cancer-predisposing syndrome 2020-06-22 criteria provided, single submitter clinical testing The c.3724_3726delCGT variant (also known as p.R1242del) is located in coding exon 8 of the MSH6 gene. This variant results from an in-frame CGT deletion at nucleotide positions 3724 to 3726. This results in the in-frame deletion of an arginine at codon 1242. This alteration was identified in an individual diagnosed with an MSH6-deficient rectal cancer at age 42 and a family history meeting the Amsterdam II criteria; this same alteration was present in this individual's brother, who was diagnosed with rectal cancer at age 53, and mother, who was diagnosed with endometrial cancer at age 54 and ascending colon cancer at age 78 (Roncari B et al. Clin. Genet. 2007 Sep;72:230-7). This alteration has also been reported in multiple other patients with a personal and/or family history consistent with Lynch syndrome, including several demonstrating loss of MSH6 protein by immunohistochemistry (IHC) analysis (Baglietto L et al. J. Natl. Cancer Inst. 2010 Feb;102:193-201; Batte BA et al. Gynecol. Oncol. 2014 Aug;134(2):319-25; Ring KL et al. Mod. Pathol. 2016 Nov;29:1381-1389; Ambry internal data). In addition, a missense variant impacting codon 1242 (p.R1242H) has been detected in trans with a pathogenic MSH6 mutation in an individual whose clinical presentation was consistent with CMMR-D due to biallelic MSH6 mutations and had isolated absence of MSH6 in both tumor and normal tissue by IHC (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
GeneDx RCV000255857 SCV000322122 likely pathogenic not provided 2017-01-17 criteria provided, single submitter clinical testing This in-frame deletion of 3 nucleotides in MSH6 is denoted c.3724_3726delCGT at the cDNA level and p.Arg1242del (R1242del) at the protein level. The normal sequence, with the bases that are deleted in brackets, is ATGT[delCGT]ACAT. This deletion of a single Arginine residue occurs at a position that is conserved across species and is located within domain V of the MutS domain (Terui 2013). This variant has been observed in individuals with endometrial and colorectal cancer, segregating with disease in at least one family, and immunohistochemistry (IHC) of two tumors revealed absence of MSH6 protein (Roncari 2007, Batte 2014). In addition, the International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant as likely pathogenic" (Thompson 2014). MSH6 Arg1242del was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Based on currently available evidence, we consider MSH6 Arg1242del to be a likely pathogenic variant."
Invitae RCV000524185 SCV000551262 pathogenic Hereditary nonpolyposis colorectal neoplasms 2020-10-30 criteria provided, single submitter clinical testing This sequence change deletes 3 nucleotides from exon 8 of the MSH6 mRNA (c.3724_3726delCGT). This leads to the deletion of 1 amino acid residue in the MSH6 protein (p.Arg1242del) but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with Lynch syndrome (PMID: 20028993) and endometrial cancer (PMID: 24933100, 27443514), and shown to segregate with colorectal cancer in 3 members of a single family (PMID: 17718861). This variant has also been reported in multiple individuals with Lynch syndrome spectrum cancers in the Universal Mutation Database (PMID: 22144684). ClinVar contains an entry for this variant (Variation ID: 89450). Based on a multifactorial likelihood algorithm using genetic and in silico data, this variant has been determined to have a high probability of being pathogenic (PMID: 24362816). A missense substitution at this codon (p.Arg1242His) has been determined to be pathogenic (PMID: 24763289, 23729658). This suggests that the arginine residue is critical for MSH6 protein function and that other variants at this position that disrupt or delete the arginine residue may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
Color Health, Inc RCV000129144 SCV000690391 likely pathogenic Hereditary cancer-predisposing syndrome 2020-04-22 criteria provided, single submitter clinical testing
Constitutional Genetics Lab,Leon Berard Cancer Center RCV001249986 SCV001424000 pathogenic Lynch-like syndrome 2019-07-01 no assertion criteria provided clinical testing

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