Submissions for variant NM_000179.3(MSH6):c.467C>G (p.Ser156Ter)

gnomAD frequency: 0.00001  dbSNP: rs63749873

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075003	SCV000108220	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
Pathway Genomics	RCV000172813	SCV000223779	pathogenic	Lynch syndrome 1	2014-10-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000201956	SCV000279092	pathogenic	not provided	2022-02-14	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; Observed in patients with Lynch-related cancers and tumor studies consistent with pathogenic variants in this gene (Wijnen 1999, Plaschke 2004, Stormorken 2005, Oeverbeek 2007, Ramsoekh 2008, van Puijenbroek 2008, Sjursen 2010, Leenan 2012, van Lier 2012, Song 2014, DeRycke 2017, Xu 2020); Not observed at a 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, 15236168, 18625694, 18301448, 22081473, 10508506, 23741719, 25345868, 25318681, 18415027, 15483016, 20587412, 17453009, 24728189, 22306203, 22274719, 16034045, 24145353, 20028993, 28514183, 24362816, 33194656, 28944238, 30013564, 30787465)
Invitae	RCV000524207	SCV000551041	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-12-15	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser156*) 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 (rs63749873, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with Lynch syndrome and rectal cancer and ovarian cancer (PMID: 10508506, 15483016, 16034045, 17453009, 18301448, 18625694, 22081473, 24728189). It is commonly reported in individuals of Dutch ancestry (PMID: 10508506, 15483016, 16034045, 17453009, 18301448, 18625694, 22081473, 24728189). ClinVar contains an entry for this variant (Variation ID: 89534). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000490955	SCV000580104	pathogenic	Hereditary cancer-predisposing syndrome	2021-11-29	criteria provided, single submitter	clinical testing	The p.S156* pathogenic mutation (also known as c.467C>G), located in coding exon 3 of the MSH6 gene, results from a C to G substitution at nucleotide position 467. This changes the amino acid from a serine to a stop codon within coding exon 3. This alteration has been identified in multiple individuals meeting Amsterdam diagnostic criteria for Lynch syndrome (Wijnen et al. Nature Genetics. 1999. Vol 23. 142-144; Overbeek et al. British Journal of Cancer. 2007. 96,1605-1612; van Lier M et al. J Pathol. 2012 Apr;226(5):764-74). Affected individuals have been reported with isolated loss of MSH6 or loss of both MSH6 and MSH2 proteins on immunohistochemistry (Steinke et al. European Journal of Human Genetics. 2208.16,587-592; Stormorken A et al. J Clin Oncol. 2005 Jul 20;23(21):4705-12). This alteration was also identified with c.1316A>G in an individual diagnosed with constitutional mismatch repair deficiency (Tesch VK et al. Front Immunol, 2018 Jul;9:1506). 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.
Counsyl	RCV000576312	SCV000677750	pathogenic	Lynch syndrome 5	2017-02-15	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000201956	SCV000888290	pathogenic	not provided	2018-04-19	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000075003	SCV000917758	pathogenic	Lynch syndrome	2019-04-15	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.467C>G (p.Ser156X) 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.718C>T (p.Arg240X), c.742C>T(p.Arg248X)). The variant allele was found at a frequency of 8e-06 in 251286 control chromosomes (gnomAD and DeRycke_2017) and has been reported in the literature in multiple individuals affected with colon cancer, pancreatic cancer and constitutional mismatch repair deficiency syndrome (Wijnen_1999, Steinke_2008, vanLier_2012, DeRycke_2017, Hu_2018, Tesch_2018). These data indicate that the variant is very likely to be associated with disease. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000201956	SCV001250444	pathogenic	not provided	2018-05-01	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000201956	SCV003820267	pathogenic	not provided	2022-01-27	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000576312	SCV004018979	pathogenic	Lynch syndrome 5	2023-03-29	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	RCV003466952	SCV004195801	pathogenic	Endometrial carcinoma	2023-05-05	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000201956	SCV000257301	pathogenic	not provided		no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357340	SCV001552786	pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	The MSH6 p.Ser156X variant was identified in 15 of 6088 proband chromosomes (frequency: 0.002) from individuals or families with HNPCC (Wijnen 1999, Steinke 2008, van Lier 2012, Hendriks 2004, Plaschke 2004, Stormorken 2005, Overbeek 2007, Ramsoekh 2008). The variant was also identified in dbSNP (ID: rs63749873) “With Pathogenic allele”, HGMD (3X), “Mismatch Repair Genes Variant Database” (7X), InSiGHT Colon Cancer Gene Variant Database (16X as “Pathogenic”), and the ClinVar database (classified as a pathogenic variant by an expert panel). Tumours with this variant were also found to be MSI-H (van Lier 2012, Overbeek 2007). This variant was also determined by extended haplotype analysis to be a founder mutation of ancient origin in the Dutch population (Ramsoekh 2008). The p.Ser156X variant leads to a premature stop codon at position 156, 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 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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000201956	SCV001744857	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000201956	SCV001964948	pathogenic	not provided		no assertion criteria provided	clinical testing
GeneReviews	RCV000172813	SCV002054078	not provided	Lynch syndrome 1		no assertion provided	literature only
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	RCV000576312	SCV004041670	pathogenic	Lynch syndrome 5	2023-10-09	no assertion criteria provided	clinical testing