Submissions for variant NM_000179.3(MSH6):c.3311_3312del (p.Phe1104fs)

dbSNP: rs267608092

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000074837	SCV000108049	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
Ambry Genetics	RCV000223509	SCV000275318	pathogenic	Hereditary cancer-predisposing syndrome	2023-11-30	criteria provided, single submitter	clinical testing	The c.3311_3312delTT pathogenic mutation, located in coding exon 5 of the MSH6 gene, results from a deletion of two nucleotides at nucleotide positions 3311 to 3312, causing a translational frameshift with a predicted alternate stop codon (p.F1104Wfs*3). This variant was described in a proband with ovarian cancer at 49 years of age, whose family history included a father with rectal cancer at 80 years and paternal first cousin with endometrial cancer at 57 years. The proband's cousin was confirmed to be positive for the variant, which established obligate carrier status in the proband's father (Suchy J et al. J. Hum. Genet. 2002;47:529-31; Suchy J et al. Clin Genet. 2006 Jul;70:68-70). This variant was also reported in a man with MSI-H colorectal cancer diagnosed at age 22 and no family history; this individual also carried an alteration in HOXB13 (p.G84E) (Akbari MR et al. Cancer Epidemiol. 2013 Aug;37(4):424-7). The c.3311_3312delTT variant has also been reported in a 60 year old woman with three synchronous primary malignancies and whose family history met Amsterdam II criteria (Mendez LE et al. Gynecol Oncol Rep. 2016 Aug;17:29-32). 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)	RCV000202034	SCV000331076	pathogenic	not provided	2016-02-04	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000630139	SCV000751095	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2025-01-25	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Phe1104Trpfs*3) 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 (rs267608092, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. 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. ClinVar contains an entry for this variant (Variation ID: 89370). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000223509	SCV000905456	pathogenic	Hereditary cancer-predisposing syndrome	2023-04-05	criteria provided, single submitter	clinical testing	This variant deletes 2 nucleotides in exon 5 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 and families affected with Lynch syndrome-associated disease (PMID: 12376742, 16813607, 23541221, 27331139). This variant has been identified in 1/251428 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.
Revvity Omics, Revvity	RCV000202034	SCV002017566	pathogenic	not provided	2019-05-05	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000009490	SCV004185680	pathogenic	Lynch syndrome 5	2023-08-22	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	RCV003460681	SCV004195558	pathogenic	Endometrial carcinoma	2023-08-25	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000202034	SCV004221218	pathogenic	not provided	2021-09-14	criteria provided, single submitter	clinical testing	This frameshift variant causes the premature termination of MSH6 protein synthesis. In addition, it has been described in individuals with endometrial cancer, ovarian cancer, and colorectal cancer in the published literature (PMID: 33746161 (2021), 30128536 (2018), 26648449 (2015), 23541221 (2013), 12376742 (2002)). Based on the available information, this variant is classified as pathogenic.
All of Us Research Program, National Institutes of Health	RCV000074837	SCV004835044	pathogenic	Lynch syndrome	2023-06-08	criteria provided, single submitter	clinical testing	This variant deletes 2 nucleotides in exon 5 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 and families affected with Lynch syndrome-associated disease (PMID: 12376742, 16813607, 23541221, 27331139). This variant has been identified in 1/251428 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.
GeneDx	RCV000202034	SCV005333651	pathogenic	not provided	2024-03-25	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: 12376742, 35475445, 28888541, 29922827)
OMIM	RCV000009490	SCV000029708	pathogenic	Lynch syndrome 5	2002-01-01	no assertion criteria provided	literature only
Mayo Clinic Laboratories, Mayo Clinic	RCV000202034	SCV000257250	pathogenic	not provided		no assertion criteria provided	research