Submissions for variant NM_000179.3(MSH6):c.2569_2572del (p.Asp857fs)

dbSNP: rs587779243

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000074755	SCV000107965	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
Genetics and Molecular Pathology, SA Pathology	RCV002272050	SCV002556814	pathogenic	Lynch syndrome 5	2021-09-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002426627	SCV002740268	pathogenic	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	clinical testing	The c.2569_2572delGATT pathogenic mutation, located in coding exon 4 of the MSH6 gene, results from a deletion of 4 nucleotides at nucleotide positions 2569 to 2572, causing a translational frameshift with a predicted alternate stop codon (p.D857Ffs*10). This mutation has been identified in multiple families with Lynch syndrome, including a 49 year-old woman with ovarian cancer and MSS endometrioid endometrial cancer that also demonstrated loss of MSH6 protein expression by IHC (Baglietto L et al. J. Natl. Cancer Inst. 2010 Feb;102:193-201; Jóri B et al. Oncotarget, 2015 Dec;6:41108-22). Of note, this mutation is also designated as p.D857fs, c.2569_2572del, and p.Asp857Phefs10* 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003477461	SCV004221182	pathogenic	not provided	2022-09-26	criteria provided, single submitter	clinical testing	This frameshift variant alters the translational reading frame of the MSH6 mRNA and causes the premature termination of MSH6 protein synthesis. org)). It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in an individual with endometrial cancer (PMID: 26517685 (2015)). It has also been reported in individuals with colorectal cancer and/or Lynch Syndrome (PMID: 20028993 (2010)). Based on the available information, this variant is classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003593870	SCV004293915	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-03-24	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 89290). This premature translational stop signal has been observed in individual(s) with clinical features of MSH6-related conditions (PMID: 20028993, 26517685). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Asp857Phefs*10) 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).
Color Diagnostics, LLC DBA Color Health	RCV002426627	SCV004357658	pathogenic	Hereditary cancer-predisposing syndrome	2022-11-01	criteria provided, single submitter	clinical testing	This variant deletes 4 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, this variant has been reported in individuals affected with Lynch Syndrome in the literature (PMID: 20028993). 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.
All of Us Research Program, National Institutes of Health	RCV000074755	SCV004830551	pathogenic	Lynch syndrome	2023-04-10	criteria provided, single submitter	clinical testing	This variant deletes 4 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, this variant has been reported in individuals affected with Lynch Syndrome in the literature (PMID: 20028993). 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353485	SCV000592610	pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	The p.Asp857PhefsX10 deletion variant has been previously reported in 2 probands with Lynch syndrome related cancers (Baglietto 2009). This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 857 and leads to a premature stop codon 10 codons downstream. This alteration is then predicted to lead to a truncated or absent protein product and loss of function. Loss of function variants are an established mechanism of disease for the MSH6 gene in Lynch syndrome. In summary, based on the above information, this variant is classified as pathogenic.
Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences	RCV001646995	SCV001852761	pathogenic	Ovarian carcinoma	2021-09-11	no assertion criteria provided	clinical testing