Submissions for variant NM_000179.3(MSH6):c.718C>T (p.Arg240Ter)

dbSNP: rs63750019

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075028	SCV000108249	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
Ambry Genetics	RCV000220361	SCV000276760	pathogenic	Hereditary cancer-predisposing syndrome	2022-05-26	criteria provided, single submitter	clinical testing	The p.R240* pathogenic mutation (also known as c.718C>T), located in coding exon 4 of the MSH6 gene, results from a C to T substitution at nucleotide position 718. This changes the amino acid from an arginine to a stop codon within coding exon 4. This mutation has been identified in two individuals with colorectal carcinoma; one individual's tumor was MSI-low and displayed isolated loss of MSH6 protein staining on IHC (Yan HL et al. Cancer Sci. 2008 Apr;99(4):770-80; DeRycke MS et al. Mol. Genet. Genomic Med. 2017 Sep;5(5):553-569). 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.
GeneDx	RCV000657653	SCV000779400	pathogenic	not provided	2023-07-14	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; Observed in individuals with personal and/or family history of Lynch-associated cancers, with most studied tumors demonstrating loss of MSH6 on immunohistochemistry (Yan et al., 2008; Sjursen et al., 2010; Kovac et al., 2011; Roberts et al., 2013); This variant is associated with the following publications: (PMID: 25525159, 18307539, 23212176, 21671081, 19526325, 27978560, 11807791, 20587412, 33452216, 33422027, 29967336, 28514183, 34815169, 32156018, Cao2023[poster], 28944238, 31830689, 33087929, 34148862, 29922827)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000704209	SCV000833148	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-12-12	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg240*) 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 (rs63750019, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with colorectal cancer or suspected of Lynch syndrome (PMID: 18307539, 28514183, 28944238). 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: 89559). Studies have shown that this premature translational stop signal is associated with inconclusive levels of altered splicing (internal data). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000075028	SCV000917786	pathogenic	Lynch syndrome	2018-12-20	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.718C>T (p.Arg240X) 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. The variant allele was found at a frequency of 4e-06 in 247068 control chromosomes (gnomAD and publication). c.718C>T has been reported in the literature in multiple individuals affected with Lynch Syndrome (Yan_2008, Sjursen_2010, Chubb_2015, Kovac_2011). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Department of Molecular Diagnostics, Institute of Oncology Ljubljana	RCV001310159	SCV001499740	pathogenic	Lynch syndrome 1	2020-04-02	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV002288564	SCV002579731	pathogenic	Lynch syndrome 5	2021-11-24	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000657653	SCV002774362	pathogenic	not provided	2021-07-16	criteria provided, single submitter	clinical testing	This variant has been identified in individuals with Lynch Syndrome and colorectal cancer in the published literature (PMIDs: 33422027 (2021), 28944238 (2017), 21671081 (2011), 20587412 (2010), and 18307539 (2008)). Additionally, tumor samples from unrelated individuals analyzed by immunohistochemistry were reported to be MSH6 deficient in the published literature (PMIDs: 21671081 (2011), 20587412 (2010), and 18307539 (2008)). Based on the available information, this variant is classified as pathogenic.
Revvity Omics, Revvity	RCV000657653	SCV003820156	pathogenic	not provided	2022-11-08	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000657653	SCV004033728	pathogenic	not provided	2023-08-01	criteria provided, single submitter	clinical testing	MSH6: PVS1, PM2
Myriad Genetics, Inc.	RCV002288564	SCV004188203	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	RCV003460701	SCV004198166	pathogenic	Endometrial carcinoma	2022-03-22	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000220361	SCV004356806	pathogenic	Hereditary cancer-predisposing syndrome	2022-09-06	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 (PMID: 18307539, 20587412, 21671081) and colorectal cancer (PMID: 28944238). This variant has been identified in 1/250994 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.
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV002288564	SCV004805555	uncertain significance	Lynch syndrome 5	2024-03-25	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000075028	SCV004848290	pathogenic	Lynch syndrome	2019-10-14	criteria provided, single submitter	clinical testing	The p.Arg240X variant in MSH6 has been previously reported in 1 individual referred for multigene panel testing (Espenschied 2017), 2 individuals with colorectal cancer, one of which was MSI-low (DeRycke 2017, Yan 2008), and 1 individual with Lynch syndrome and segregated with disease in 2 affected family members (Kovac 2011). It was also identified in 1/30606 of South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant was classified as Pathogenic on September 5, 2013 by the ClinGen-approved InSiGHT expert panel (Variation ID 89559). This nonsense variant leads to a premature termination codon at position 240, 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.
All of Us Research Program, National Institutes of Health	RCV000075028	SCV005429222	pathogenic	Lynch syndrome	2024-05-14	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 (PMID: 18307539, 20587412, 21671081, 33422027) and colorectal cancer (PMID: 28944238). This variant has been identified in 1/250994 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.
Genomics and Molecular Medicine Service, East Genomic Laboratory Hub, NHS Genomic Medicine Service	RCV005237500	SCV005882931	pathogenic	Inherited MMR deficiency (Lynch syndrome)	2024-11-13	criteria provided, single submitter	clinical testing	PVS1,PS4_Very Strong,PM2_Supporting,PP4
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358367	SCV001554079	pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	The MSH6 p.Arg240* variant was identified in 6 of 3374 proband chromosomes (frequency: 0.002) from individuals or families with colon or colorectal cancer and was not identified in 96 control chromosomes from healthy individuals (Berginc 2009, Ohmiya 2001, Pearlman 2017, Plaschke 2002, Sjursen 2010, Yan 2008). The variant was also identified in the following databases: dbSNP (ID: rs63750019) as "With Pathogenic allele", ClinVar (2x pathogenic), Clinvitae (2x pathogenic), Cosmic (1x, malignant melanoma), UMD-LSDB (1x, causal biological significance), Insight Colon Cancer Gene Variant Database (3x, pathogenic), Mismatch Repair Genes Variant Database, and the Insight Hereditary Tumors Database (3x, pathogenic, somatic and germline origins). The variant was not identified in MutDB or the Zhejiang Colon Cancer Database. The variant was identified in control databases in 1 of 245758 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). Observations by population include South Asian in 1 of 30772 chromosomes (freq: 0.00003); the variant was not observed in the African, “Other”, Latino, European, Ashkenazi Jewish, East Asian, or Finnish populations. In addition to being a germline variant, multiple studies have found the c.718C>T variant occurs as a somatic mutation in colon tumor tissue, often accompanied by microsatellite instability and lack of MSH6 expression (Berginc 2009, Ohmiya 2001, Pearlman 2017, Plaschke 2002). The c.718C>T variant leads to a premature stop codon at position 240, which is predicted to lead to 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 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.