Submissions for variant NM_000179.3(MSH6):c.742C>T (p.Arg248Ter)

dbSNP: rs63749980

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075032	SCV000108253	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
Invitae	RCV000524215	SCV000253781	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-09-11	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: 89563). This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 10508506, 18301448). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg248*) 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).
GeneDx	RCV000486750	SCV000566643	pathogenic	not provided	2022-01-28	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; Observed in individuals with a personal and/or family history of MSH6-related cancers (Wijnen 1999, Steinke 2008, Tsukanov 2021); 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: 25525159, 33087929, 33937060, 30787465, 10508506, 15236168, 12547705, 20028993, 18301448, 29625052, 28502729)
Ambry Genetics	RCV000490932	SCV000580084	pathogenic	Hereditary cancer-predisposing syndrome	2021-07-30	criteria provided, single submitter	clinical testing	The p.R248* pathogenic mutation (also known as c.742C>T), located in coding exon 4 of the MSH6 gene, results from a C to T substitution at nucleotide position 742. This changes the amino acid from an arginine to a stop codon within coding exon 4. This alteration has been reported in multiple individuals with Lynch syndrome-associated cancers (Wijnen J et al. Nat. Genet. 1999 Oct;23(2):142-4; Steinke V et al. Eur. J. Hum. Genet. 2008 May;16(5):587-92; Chao X et al. Cancer Commun (Lond), 2019 07;39:42; Tsukanov AS et al. Front Oncol, 2021 Apr;11:652696). In one study, authors reported this pathogenic mutation in an individual diagnosed with colon cancer at age 26 whose tumor showed high microsatellite instability and absent MSH6 staining on IHC (Hendriks Y et al. Am. J. Pathol. 2003 Feb;162(2):469-77). Additionally, this variant was reported in 1/60,466 breast cancer cases and in 0/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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	RCV000486750	SCV001134456	pathogenic	not provided	2019-03-25	criteria provided, single submitter	clinical testing	The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and not found in general population data.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193103	SCV001361712	pathogenic	Hereditary nonpolyposis colon cancer	2023-12-04	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.742C>T (p.Arg248X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. c.892C>T, p.Arg298X; c.1135_1139delAGAGA, p.Arg379X; c.1190_1191delAT, p.Tyr397fsX3). The variant was absent in 276846 control chromosomes (gnomAD). c.742C>T has been reported in the literature in individuals affected with Lynch Syndrome; analysis of tumor samples showed loss of MSH6 protein expression via immunohistochemistry and high microsatellite instability (Tsukanov_2021, Steinke_2008, Hendriks_2003, Wijnen_1999). These data indicate that the variant is likely associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 12547705, 15236168, 28152038, 18301448, 33937060, 10508506). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014; all submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Sema4, Sema4	RCV000490932	SCV002536352	pathogenic	Hereditary cancer-predisposing syndrome	2021-04-13	criteria provided, single submitter	curation
MGZ Medical Genetics Center	RCV002288565	SCV002581332	pathogenic	Lynch syndrome 5	2022-02-09	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000486750	SCV002760657	pathogenic	not provided	2023-08-15	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV002288565	SCV004188230	pathogenic	Lynch syndrome 5	2023-08-10	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	RCV003460702	SCV004198112	pathogenic	Endometrial carcinoma	2022-11-22	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000486750	SCV004226587	pathogenic	not provided	2023-03-30	criteria provided, single submitter	clinical testing	PP4, PP5, PM2, PVS1
Color Diagnostics, LLC DBA Color Health	RCV000490932	SCV004357555	pathogenic	Hereditary cancer-predisposing syndrome	2023-02-01	criteria provided, single submitter	clinical testing	This variant changes 1 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, with tumor analyses showing microsatellite instability and/or loss of MSH6 protein by immunohistochemistry analyses (PMID: 10508506, 12547705, 18301448, 33937060). 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	RCV000075032	SCV004836941	pathogenic	Lynch syndrome	2023-04-10	criteria provided, single submitter	clinical testing	This variant changes 1 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, with tumor analyses showing microsatellite instability and/or loss of MSH6 protein by immunohistochemistry analyses (PMID: 10508506, 12547705, 18301448, 33937060). 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000075032	SCV004847854	pathogenic	Lynch syndrome	2019-10-14	criteria provided, single submitter	clinical testing	The p.Arg248X variant in MSH6 has been previously reported in 1 individual with Lynch syndrome (Steinke 2008) and 2 individuals with colorectal cancer (Wijnen 1999, Hendricks 2003). It was absent from large population studies. This variant was classified as Pathogenic on September 5, 2013 by the ClinGen-approved InSiGHT expert panel (Variation ID 89563). This nonsense variant leads to a premature termination codon at position 248, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the MSH6 gene is an established disease mechanism in individuals with Lynch syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP criteria applied: PVS1, PM2, PS4_Supporting.