ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1223A>G (p.Tyr408Cys) (rs63750379)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000590753 SCV000149407 uncertain significance not provided 2017-05-22 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.1223A>G at the cDNA level, p.Tyr408Cys (Y408C) at the protein level, and results in the change of a Tyrosine to a Cysteine (TAT>TGT). This variant was observed in at least one individual with sporadic gastric cancer (Fan 2006, Zhang 2006). According to the International Society for Gastrointestinal Hereditary Tumours (InSiGHT) database, MSH2 Tyr408Cys is an uncertain variant based on insufficient evidence. MSH2 Tyr408Cys was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Tyrosine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH2 Tyr408Cys occurs at a position that is conserved across species and is located within the lever domain in the region of interaction with MSH6 and MSH3 (L?tzen 2008, Kansikas 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether MSH2 Tyr408Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000076070 SCV000260803 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-08-25 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 408 of the MSH2 protein (p.Tyr408Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with gastric cancer (PMID: 16929514). ClinVar contains an entry for this variant (Variation ID: 90574). Experimental studies have shown that this missense change is associated with decreased growth in vitro (PMID: 29731845). 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.
Ambry Genetics RCV000571404 SCV000669785 uncertain significance Hereditary cancer-predisposing syndrome 2019-09-11 criteria provided, single submitter clinical testing Insufficient evidence
Color RCV000571404 SCV000689964 uncertain significance Hereditary cancer-predisposing syndrome 2019-06-12 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000590753 SCV000696201 uncertain significance not provided 2017-04-20 criteria provided, single submitter clinical testing Variant summary: The MSH2 c.1223A>G (p.Tyr408Cys) variant located in the DNA mismatch repair protein MutS, core domain (via InterPro) involves the alteration of a conserved nucleotide and 4/4 in silico tools (SNPsandGO not captured due to low reliability index) predict a damaging outcome. However, publications provide conflicting information as to whether the missense change will affect protein function: Ali_2012 indicates the variant plays a key role in the ionic interaction with E455 in another alpha-helix is removed, while Fan_2006 indicates "both tyrosine and cysteine are uncharged amino acids, and this region is not conserved and according to structure modeling, the substitution of tyrosine and cysteine makes no difference in the H-bonds." This variant is absent in 121524 control chromosomes (ExAC and publication controls). A publication, Fan_2006, cites the variant to have been found in a sporadic gastric cancer pt, although with limited information (lack of co-occurrence and cosegregation data). A functional yeast study presented in Chinese indicates in the translated abstract that the variant of interest grew slower and could affect MSH2 function, however, additional studies need to be performed to support this finding. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Therefore, until additional information becomes available (ie, clinical and functional studies), the variant of interest has been classified as a "Variant of Uncertain Significance (VUS)."
Institute of Human Genetics, University of Leipzig Medical Center RCV001253505 SCV001429243 uncertain significance Turcot syndrome 2019-12-10 criteria provided, single submitter clinical testing

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