Submissions for variant NM_000179.3(MSH6):c.1421_1422dup (p.Gln475fs)

dbSNP: rs63750854

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000074655	SCV000107857	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
Ambry Genetics	RCV000222326	SCV000276852	pathogenic	Hereditary cancer-predisposing syndrome	2022-08-15	criteria provided, single submitter	clinical testing	The c.1421_1422dupTG pathogenic mutation, located in coding exon 4 of the MSH6 gene, results from a duplication of TG at nucleotide position 1421, causing a translational frameshift with a predicted alternate stop codon (p.Q475Cfs*7). This mutation has been reported in multiple individuals with Lynch syndrome (Plaschke J et al. Int. J. Cancer. 2002 Feb;97:643-8; Steinke V et al. Eur. J. Hum. Genet. 2008 May;16:587-92; Kunstmann E et al. BMC Med. Genet. 2004 Jun;5:16; Moline J et al. Gynecol. Oncol. 2013 Jul;130:121-6). Additionally, this mutation has been reported in trans with another pathogenic MSH6 mutation in a sibling pair with constitutional mismatch repair-deficiency (CMMR-D) syndrome (Jasperson KW et al. Clin Genet. 2011;80:394–397). Of note, this alteration is also designated as nt1510insTG and c.1422_1423insTG in published literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000540977	SCV000624646	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2025-01-10	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln475Cysfs*7) in the MSH6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). This variant is present in population databases (rs63750854, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with rectal cancer, breast cancer, adenomatous polyps, and cafe au lait macules (PMID: 11807791, 15483016, 21039432, 27616075). Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this MSH6 variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 1,370,736 individuals referred to our laboratory for MSH6 testing. This variant is also known as 1510insTG. ClinVar contains an entry for this variant (Variation ID: 89193). For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759125	SCV000888238	pathogenic	not provided	2023-07-12	criteria provided, single submitter	clinical testing	The MSH6 c.1421_1422dup (p.Gln475Cysfs*7) variant alters the translational reading frame of the MSH6 mRNA and causes the premature termination of MSH6 protein synthesis. In the published literature, this variant has been reported in multiple individuals and families with Lynch syndrome-associated cancers in the published literature (PMIDs: 28944238 (2017), 27616075 (2016), 25430799 (2015), 18301448 (2008), 15483016 (2004), 11807791 (2002)). In addition, it has been reported in trans with another MSH6 variant in siblings with constitutional mismatch repair deficiency syndrome (PMID: 21039432 (2011)). Based on the available information, this variant is classified as pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV001253395	SCV001429077	pathogenic	Lynch syndrome 5	2018-07-03	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000222326	SCV001735708	pathogenic	Hereditary cancer-predisposing syndrome	2021-04-05	criteria provided, single submitter	clinical testing	This variant inserts 2 nucleotides in exon 4 of the MSH6 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with Lynch syndrome or suspected Lynch syndrome (PMID: 15483016, 15217520, 18301448, 21039432, 25430799, 27273229, 31822864), breast/ovarian cancer (PMID: 23612316, 27153395, 27616075). This variant has been identified in 1/251168 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH6 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Myriad Genetics, Inc.	RCV001253395	SCV004188200	pathogenic	Lynch syndrome 5	2023-08-14	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Baylor Genetics	RCV003460661	SCV004195637	pathogenic	Endometrial carcinoma	2023-07-26	criteria provided, single submitter	clinical testing