ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2005G>T (p.Gly669Cys) (rs63751668)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000566809 SCV000676071 uncertain significance Hereditary cancer-predisposing syndrome 2016-01-20 criteria provided, single submitter clinical testing The c.2005G>T variant (also known as p.G669C), located in coding exon 12 of the MSH2 gene, results from a G to T substitution at nucleotide position 2005. This change occurs in the last base pair of coding exon 12, which makes it likely to have some effect on normal mRNA splicing. In addition to potential splicing impact, this alteration would change the glycine at codon 669 to cysteine, an amino acid with highly dissimilar properties. This nucleotide change has not been reported in the literature to date, however different nucleotide changes at the same location, c.2005G>A and c.2005G>C, were identified in patients with tumors lacking MSH2 expression on IHC (Zahary MN et al. World J. Gastroenterol. 2012 Feb; 18(8):814-20; Losi L et al. Am. J. Gastroenterol. 2005 Oct; 100(10):2280-7). Both the nucleotide and amino acid positions are highly conserved in available vertebrate species. This alteration is predicted by the BDGP splice site prediction tool to abolish the native splice donor site, but is predicted to weaken (but not abolish) the efficiency of the native splice donor site by ESEfinder; however, direct evidence experimental is unavailable. The amino acid change is predicted to be probably damaging and deleterious by PolyPhen and SIFT in silico analyses, respectively. In addition, the amino acid change is predicted to be deleterious by MAPP-MMR in silico analyses (Chao E et al. Hum Mutat. 2008 Jun;29(6):852-60) and pathogenic by PON-MMR in silico analyses (Ali H et al. Hum. Mutat. 2012 Apr; 33(4):642-50). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Health, Inc RCV000566809 SCV000690038 likely pathogenic Hereditary cancer-predisposing syndrome 2018-10-17 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000781556 SCV000919694 uncertain significance not specified 2018-03-28 criteria provided, single submitter clinical testing Variant summary: MSH2 c.2005G>T (p.Gly669Cys) variant involves the alteration of a conserved last nucleotide of exon 12. Several computational tools predict a significant impact on normal splicing: Five predict the variant abolishes a 5 splicing donor site. If transcribed without splice alteration, the variant would result in a non-conservative amino acid change located in the loop region within Walker boxes in ATPase domain (domain V) in the encoded protein sequence, with five of five in-silico tools predicting damaging effect of the variant on protein function. However these predictions have yet to be confirmed by functional studies. The variant was absent in 243882 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2005G>T in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. However, a different variant affecting the same nucleotide position (c.2005G>C, p.Gly669Arg) was reported to be found in 2 LS patients who showed absent expression of MSH2 protein by immunohistochemistry; this report might indicate the importance of this nucleotide- or amino acid position (PMID: 22371642). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Invitae RCV001069626 SCV001234805 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-11-28 criteria provided, single submitter clinical testing This sequence change replaces glycine with cysteine at codon 669 of the MSH2 protein (p.Gly669Cys). The glycine residue is highly conserved and there is a large physicochemical difference between glycine and cysteine. This variant also falls at the last nucleotide of exon 12 of the MSH2 coding sequence, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual in the Universal Mutation Database (Unpublished data). ClinVar contains an entry for this variant (Variation ID: 486870). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001355386 SCV001550260 likely pathogenic Carcinoma of colon no assertion criteria provided clinical testing The MSH2 c.2005G>T variant was not identified in the literature nor was it identified in dbSNP, ClinVar, MutDB, LOVD 3.0, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, or Insight Hereditary Tumors Database. The variant was identified in Cosmic (1x in liver cancer), UMD-LSDB (1x as likely causal). The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.2005G>T variant occurs in the last three bases of the exon. This position has been shown to be part of the splicing consensus sequence and variants involving this position sometimes affect splicing. In addition, 5 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic.

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