Submissions for variant NM_000179.3(MSH6):c.1637_1638del (p.Glu546fs)

dbSNP: rs267608076

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000074676	SCV000107879	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
GeneDx	RCV000217244	SCV000279610	pathogenic	not provided	2023-01-15	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as c.1635_1636delAG; This variant is associated with the following publications: (PMID: 16885385, 20028993, 25559809, 30787465, 29489754, 26787237, 30256826)
Invitae	RCV000529714	SCV000624672	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-12-16	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu546Glyfs*16) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Lynch syndrome-associated cancers (PMID: 16885385, 20028993, 25559809, 26787237). This variant is also known as c.1635_1636delAG. ClinVar contains an entry for this variant (Variation ID: 89213). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000575511	SCV000662350	pathogenic	Hereditary cancer-predisposing syndrome	2021-02-12	criteria provided, single submitter	clinical testing	The c.1637_1638delAG pathogenic mutation, located in coding exon 4 of the MSH6 gene, results from a deletion of two nucleotides at nucleotide positions 1637 to 1638, causing a translational frameshift with a predicted alternate stop codon (p.E546Gfs*16). This pathogenic mutation has been reported in individuals with personal and family histories of Lynch syndrome related cancers (Hampel H et al. Cancer Res. 2006 Aug; 66(15):7810-7; Chubb D et al. J. Clin. Oncol. 2015 Feb; 33(5):426-32; Meric-Bernstam F et al. Ann. Oncol. 2016 May; 27(5):795-800; Martin-Morales L et al. PLoS One, 2018 Sep;13:e0203885). Of note, this alteration is also designated as c.1635_1636delAG in published 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003317076	SCV000695790	pathogenic	Hereditary nonpolyposis colon cancer	2023-06-07	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.1637_1638delAG (p.Glu546GlyfsX16) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 251216 control chromosomes (gnomAD, v2.1). c.1637_1638delAG has been reported in the literature in individuals affected with Lynch syndrome (e.g., Baglietto_2010, Chubb_2015, Hampel_2006). These data indicate that the variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 16885385, 20028993, 25559809). Six ClinVar submitters (evaluation after 2014) have cited the variant, and all submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000575511	SCV001351147	pathogenic	Hereditary cancer-predisposing syndrome	2023-12-04	criteria provided, single submitter	clinical testing	This variant deletes 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. This variant has been reported in individuals affected with Lynch syndrome and Lynch syndrome-associated disease (PMID: 16885385, 20028993, 25559809, 26787237, 27329137, 30256826). This variant has not been identified 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.
Revvity Omics, Revvity	RCV000217244	SCV003820278	pathogenic	not provided	2022-11-11	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003450929	SCV004188313	pathogenic	Lynch syndrome 5	2023-08-15	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	RCV003466934	SCV004196345	pathogenic	Endometrial carcinoma	2021-11-29	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000074676	SCV004841791	pathogenic	Lynch syndrome	2023-10-31	criteria provided, single submitter	clinical testing	This variant deletes 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. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in families affected with Lynch syndrome-associated cancers (PMID: 16885385, 20028993, 25559809). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH6 function is a known mechanism of disease. Based on available evidence, this variant is classified as Pathogenic.
Laboratory for Genotyping Development, RIKEN	RCV003162470	SCV002758359	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research