Submissions for variant NM_000251.3(MSH2):c.163del (p.Arg55fs)

dbSNP: rs63750337

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076209	SCV000107226	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation introducing premature termination codon
Invitae	RCV001059525	SCV001224151	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-10-05	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg55Glyfs*9) 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 clinical features of Lynch syndrome (PMID: 23047549, 24323032). ClinVar contains an entry for this variant (Variation ID: 90712). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193898	SCV001363058	pathogenic	Hereditary nonpolyposis colon cancer	2019-10-17	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.163delC (p.Arg55GlyfsX9) 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 232470 control chromosomes. c.163delC has been reported in the literature in individuals affected with Hereditary Non-Polyposis Colon Cancer as well as breast, ovarian and endometrial cancer (Buchanan_2014, Buerki_2012, Pal_2012, Rey_2004). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx	RCV001577449	SCV001804828	pathogenic	not provided	2019-05-07	criteria provided, single submitter	clinical testing	Frameshift 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); This variant is associated with the following publications: (PMID: 12658575, 15571801, 19123071, 22034109, 24323032, 23047549)
Ambry Genetics	RCV002390228	SCV002703049	pathogenic	Hereditary cancer-predisposing syndrome	2021-12-04	criteria provided, single submitter	clinical testing	The c.163delC pathogenic mutation, located in coding exon 1 of the MSH2 gene, results from a deletion of one nucleotide at nucleotide position 163, causing a translational frameshift with a predicted alternate stop codon (p.R55Gfs*9). This mutation has been seen in multiple unrelated individuals with HNPCC-associated cancers (Wagner A et al Am. J. Hum. Genet. 2003 May;72(5):1088-100; Pal T et al Br. J. Cancer. 2012 Nov;107(10):1783-90; Buerki N et al. Genes Chromosomes Cancer. 2012 Jan;51(1):83-91; Buchanan DD et al J. Clin. Oncol. 2014 Jan;32(2):90-100; Chubb D et al. Nat Commun. 2016 06;7:11883). Of note, this variant may be referred to as c.161delC in some literature. 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.
Myriad Genetics, Inc.	RCV003452844	SCV004187913	pathogenic	Lynch syndrome 1	2023-07-26	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000076209	SCV000592453	pathogenic	Lynch syndrome		no assertion criteria provided	clinical testing	The p.Arg55GlyfsX9 deletion variant was identified in 2 of 3798 proband chromosomes (frequency: 0.001) from individuals with ovarian or colon cancer (Pal 2012, Rey 2004), with high microsatellite instability noted in the colon tumour from the individual studied by Rey (2004). This variant was also identified in the HGMD, UMD, “InSiGHT Colon Cancer Database” and the “Mismatch Repair Genes Variant Database”. The p.Arg55GlyfsX9 variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 55 and leads to a premature stop codon 9 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function, 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.