Submissions for variant NM_000179.3(MSH6):c.3487G>T (p.Glu1163Ter)

gnomAD frequency: 0.00001  dbSNP: rs587779267

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000074867	SCV000108079	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
GeneDx	RCV000115417	SCV000149326	pathogenic	not provided	2022-12-20	criteria provided, single submitter	clinical testing	Nonsense 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: 30322717, 26437257, 26681312, 30787465, 25093288, 28874130)
Invitae	RCV000791426	SCV000551275	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-06-27	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: 89399). This premature translational stop signal has been observed in individual(s) with colon cancer, ovarian cancer or endometrial cancer (PMID: 25093288, 26437257, 26681312). This variant is present in population databases (rs587779267, gnomAD 0.007%). This sequence change creates a premature translational stop signal (p.Glu1163*) 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).
Ambry Genetics	RCV000491292	SCV000580168	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-23	criteria provided, single submitter	clinical testing	The p.E1163* pathogenic mutation (also known as c.3487G>T), located in coding exon 6 of the MSH6 gene, results from a G to T substitution at nucleotide position 3487. This changes the amino acid from a glutamic acid to a stop codon within coding exon 6. This mutation has previously been reported in a woman with synchronous primary endometrial and endometrioid ovarian cancers, where the ovarian tumor showed loss of MSH6 protein expression by IHC analysis (Vierkoetter KR et al. Gynecol. Oncol. 2014 Oct;135:81-4). It has also been observed in another patient with ovarian cancer (Susswein LR et al. Genet. Med. 2016 Aug;18:823-32) and in a Brazilian patient with early-onset colon cancer (Carneiro da Silva F. PLoS ONE. 2015 Oct;10:e0139753). 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.
A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center	RCV000074867	SCV000914311	pathogenic	Lynch syndrome	2019-01-30	criteria provided, single submitter	research
Myriad Genetics, Inc.	RCV003450970	SCV004187402	pathogenic	Lynch syndrome 5	2023-08-24	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Baylor Genetics	RCV003466948	SCV004195733	pathogenic	Endometrial carcinoma	2023-06-14	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000074867	SCV004821995	pathogenic	Lynch syndrome	2023-12-21	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 6 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 affected with Lynch syndrome associated cancer, including early onset colorectal cancer (PMID: 26437257), endometrial cancer displaying loss of MSH6 protein by immunohistochemistry analysis (PMID: 25093288), and ovarian cancer (PMID: 26681312). The individual affected with ovarian cancer also carried a pathogenic variant in the BARD1 gene (PMID: 26681312). This variant has been identified in 1/31402 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000115417	SCV000691939	pathogenic	not provided		no assertion criteria provided	clinical testing