Submissions for variant NM_000251.3(MSH2):c.1223A>G (p.Tyr408Cys)

gnomAD frequency: 0.00001  dbSNP: rs63750379

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000590753	SCV000149407	uncertain significance	not provided	2023-03-30	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18383312, 22290698, 23760103, 16929514, 17011982, 24078570, 33471991, 31237724, 33357406, 29731845, 18822302, 21120944)
Invitae	RCV000076070	SCV000260803	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-10-16	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 408 of the MSH2 protein (p.Tyr408Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with gastric cancer (PMID: 16929514). ClinVar contains an entry for this variant (Variation ID: 90574). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33357406) indicates that this missense variant is not expected to disrupt MSH2 function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on MSH2 function (PMID: 29731845, 33357406). 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	2023-01-11	criteria provided, single submitter	clinical testing	The p.Y408C variant (also known as c.1223A>G), located in coding exon 7 of the MSH2 gene, results from an A to G substitution at nucleotide position 1223. The tyrosine at codon 408 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been detected in an individual with sporadic gastric cancer (Fan Y et al. Cancer Genet Cytogenet. 2006 Oct 15;170(2):121-8). Structural modeling suggests that this alteration disrupts ionic interaction with a neighboring residue; however, direct experimental evidence of pathogenicity was not available (Ali H et al. Hum. Mutat. 2012 Apr;33(4):642-50.) Yeast-two hybridization assay demonstrated plasmids with this alteration have slow growth compared to wild type, indicating that this alteration partially affects the function of hMSH2 (Zhang X et al. Oncol Lett. 2018 May;15:6275-6282). In a massively parallel cell-based functional assay testing susceptibility to a DNA damaging agent, 6-thioguanine (6-TG), this variant was reported to be functionally neutral (Jia X et al. Am J Hum Genet, 2021 Jan;108:163-175). In addition, a study of the functional significance of MSH2 missense variants using CRISPR-Cas9 gene editing in human embryonic stem cells suggests this alteration is proficient at DNA repair function, damage response signaling and protein stability (Rath A et al. Hum Mutat, 2019 Nov;40:2044-2056). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000571404	SCV000689964	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-24	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with cysteine at codon 408 of the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). In another functional study, this variant had no impact on protein stability, DNA damage response signaling, or DNA repair function (PMID: 31237724). This variant has been reported in an individual affected with gastric cancer (PMID: 16929514, 17011982). In a large breast cancer case-control study, this variant has been reported in 1/60466 cases and 0/53461 unaffected controls (PMID: 33471991). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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	Mismatch repair cancer syndrome 1	2019-12-10	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000571404	SCV002528823	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-09	criteria provided, single submitter	curation
Baylor Genetics	RCV003466963	SCV004194553	uncertain significance	Lynch syndrome 1	2023-06-09	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997144	SCV004832624	uncertain significance	Lynch syndrome	2023-12-18	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with cysteine at codon 408 of the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). In another functional study, this variant had no impact on protein stability, DNA damage response signaling, or DNA repair function (PMID: 31237724). This variant has been reported in an individual affected with gastric cancer (PMID: 16929514, 17011982). In a large breast cancer case-control study, this variant has been reported in 1/60466 cases and 0/53461 unaffected controls (PMID: 33471991). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.