Submissions for variant NM_000251.3(MSH2):c.1861C>T (p.Arg621Ter)

dbSNP: rs63750508

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076305	SCV000107327	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation introducing premature termination codon
Invitae	RCV000524364	SCV000260744	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-11-24	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg621*) in the MSH2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Lynch syndrome and colorectal cancer (PMID: 8566964, 12624141, 17569143, 18772310, 20007843, 21598002, 21642682, 24415873). ClinVar contains an entry for this variant (Variation ID: 90804). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000414448	SCV000490618	pathogenic	not provided	2020-12-01	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 in large population cohorts (Lek et al., 2016) Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database Observed in patients with Lynch-related cancers and tumor studies consistent with pathogenic variants in this gene (Maliaka 1996, Parc 2003, Zavodna 2006, Overbeek 2007, Papp 2007, van Puijenbroek 2008, Bonadona 2011, Brieger 2011, Everett 2014, Kury 2014, Vierkoetter 2014, Goodfellow 2015, Sunga 2017, Jiang 2019, Rashid 2019) This variant is associated with the following publications: (PMID: 31615790, 32658311, 31660093, 30521064, 29489754, 28944238, 17453009, 28874130, 27863258, 25093288, 26552419, 16830052, 25504677, 23741719, 18415027, 24415873, 21642682, 21598002, 20007843, 18772310, 12624141, 28449805, 25525159, 25006859, 17569143, 8566964)
Ambry Genetics	RCV000491286	SCV000580383	pathogenic	Hereditary cancer-predisposing syndrome	2021-10-21	criteria provided, single submitter	clinical testing	The p.R621* pathogenic mutation (also known as c.1861C>T), located in coding exon 12 of the MSH2 gene, results from a C to T substitution at nucleotide position 1861. This changes the amino acid from an arginine to a stop codon within coding exon 12. This mutation has been reported in multiple HNPCC/Lynch syndrome families; several who meet Amsterdam criteria and/or have tumors that demonstrated loss of MSH2 and MSH6 by IHC (Maliaka YK et al. Hum. Genet. 1996 Feb;97(2):251-5; Weber TK et al. Cancer Res. 1997 Sep;57(17):3798-803; Niessen RC et al. Gut 2006 Dec;55(12):1781-8; Overbeek LIH et al. Br. J. Cancer. 2007 May;96(10):1605-1612; Papp J et al. World J. Gastroenterol. 2007 May;13(19):2727-32; Vierkoetter KR et al. Gynecol Oncol, 2014 Oct;135:81-4; Kang SY et al. Int J Cancer, 2015 Apr;136:1568-78; Dominguez-Valentin M et al. Front Oncol, 2016 Aug;6:189; Jiang W et al. Int J Cancer, 2019 05;144:2161-2168; Rashid MU et al. Hered Cancer Clin Pract, 2019 Oct;17:29; Wischhusen JW et al. Cancer Epidemiol Biomarkers Prev, 2020 01;29:193-199; Shao D et al. Cancer Sci, 2020 Feb;111:647-657; Yanus GA et al. Eur J Med Genet, 2020 Mar;63:103753; Akcay IM et al. Int J Cancer, 2021 01;148:285-295). 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	RCV000414448	SCV000601443	pathogenic	not provided	2017-05-22	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000491286	SCV000684988	pathogenic	Hereditary cancer-predisposing syndrome	2022-05-06	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 12 of the MSH2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with Lynch syndrome or suspected of having Lynch syndrome (PMID: 8566964, 12624141, 17569143, 18772310, 20007843, 21598002, 21642682, 27629256), or colorectal cancer (PMID: 24415873, 26552419, 29967336). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001328039	SCV000696226	pathogenic	Hereditary nonpolyposis colon cancer	2021-03-04	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.1861C>T (p.Arg621X) 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. The variant was absent in 251474 control chromosomes. c.1861C>T has been reported in the literature in multiple individuals affected with MSH2-associated cancers (Maliaka_1996, Papp_2007, Bonadona_2011, Vierkoetter_2014, Kang_2015, Dominguez-Valentin_2016). These data indicate that the variant is very likely to be associated with disease. Seven 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.
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000602838	SCV000744278	pathogenic	Lynch syndrome 1	2015-09-21	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763492	SCV000894278	pathogenic	Lynch syndrome 1; Mismatch repair cancer syndrome 1; Muir-Torré syndrome	2018-10-31	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000414448	SCV002017561	pathogenic	not provided	2019-10-29	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000491286	SCV002534419	pathogenic	Hereditary cancer-predisposing syndrome	2021-02-06	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000602838	SCV004187924	pathogenic	Lynch syndrome 1	2023-08-04	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	RCV000602838	SCV004196206	pathogenic	Lynch syndrome 1	2023-10-08	criteria provided, single submitter	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000602838	SCV000734202	pathogenic	Lynch syndrome 1		no assertion criteria provided	clinical testing
Constitutional Genetics Lab, Leon Berard Cancer Center	RCV001249915	SCV001423932	pathogenic	Lynch-like syndrome	2019-07-01	no assertion criteria provided	clinical testing
Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences	RCV001650893	SCV001870403	pathogenic	Breast carcinoma	2021-09-12	no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000414448	SCV001956297	pathogenic	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000414448	SCV002035462	pathogenic	not provided		no assertion criteria provided	clinical testing