Submissions for variant NM_000179.3(MSH6):c.2062_2063del (p.Val688fs)

dbSNP: rs63750075

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000074711	SCV000107918	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
Ambry Genetics	RCV000165752	SCV000216496	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-26	criteria provided, single submitter	clinical testing	The c.2062_2063delGT pathogenic mutation, located in coding exon 4 of the MSH6 gene, results from a deletion of two nucleotides at nucleotide positions 2062 to 2063, causing a translational frameshift with a predicted alternate stop codon (p.V688Lfs*9). This mutation was reported in a German patient with MSI-H, MSH2/MSH6-absent colorectal cancer at age 45 and whose family history met Amsterdam criteria (Steinke V et al. Eur. J. Hum. Genet. 2008 May;16:587-92). This mutation was also observed in 1/369 Swedish Lynch syndrome families (Lagerstedt-Robinson K et al. Oncol. Rep. 2016 Nov;36(5):2823-2835), and in a patient with microprolactinoma at age 39 and endometrial cancer at age 49 (Bengtsson D et al. J. Clin. Endocrinol. Metab. 2017 11;102(11):3928-3932). 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.
Eurofins Ntd Llc (ga)	RCV000592291	SCV000703737	pathogenic	not provided	2016-11-15	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000165752	SCV000905453	pathogenic	Hereditary cancer-predisposing syndrome	2023-10-05	criteria provided, single submitter	clinical testing	This variant deletes one nucleotide in exon 4 of the MSH6 gene, creating a 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 and families affected with Lynch syndrome (PMID: 11807791, 15483016, 18301448, 27601186) and Lynch syndrome-associated cancers (PMID: 28938458). This variant has also been identified in an individual affected with breast cancer (PMID: 30128536). 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.
Invitae	RCV001049192	SCV001213231	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2021-11-02	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: 89247). This variant is also known as 2149delGT (696Stop). This premature translational stop signal has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 11807791, 15483016, 27601186). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Val688Leufs*9) 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).
Department of Molecular Diagnostics, Institute of Oncology Ljubljana	RCV001310160	SCV001499741	pathogenic	Lynch syndrome 1	2020-04-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000592291	SCV002820370	pathogenic	not provided	2022-07-14	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; This variant is associated with the following publications: (PMID: 27601186, 29739316, 11807791, 30128536, 28938458, 18301448, 18269114, 24362816, 15483016)
Myriad Genetics, Inc.	RCV003450939	SCV004185665	pathogenic	Lynch syndrome 5	2023-08-16	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	RCV003466938	SCV004195836	pathogenic	Endometrial carcinoma	2023-02-12	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000074711	SCV004843779	pathogenic	Lynch syndrome	2023-12-18	criteria provided, single submitter	clinical testing	This variant deletes one nucleotide in exon 4 of the MSH6 gene, creating a 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 and families affected with Lynch syndrome (PMID: 11807791, 15483016, 18301448, 27601186) and Lynch syndrome-associated cancers (PMID: 28938458). This variant has also been identified in an individual affected with breast cancer (PMID: 30128536). 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	RCV001353545	SCV000592597	pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	The MSH6 p.Val688LeufsX9 variant was identified in 1 of 1412 proband chromosomes (frequency: 0.001) from individuals or families with Lynch Syndrome (Plaschke 2004). The variant was identified in dbSNP (ID: rs63750075) “With Pathogenic allele”, HGMD, InSiGHT Colon Cancer Database, the ClinVar database (classified as a pathogenic variant by InSIGHT) and UMD (1X as a pathogenic variant). The p.Val688LeufsX9 deletion variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 688 and leads to a premature stop codon 9 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the MSH6 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.