Submissions for variant NM_000251.3(MSH2):c.2726A>T (p.Lys909Ile)

dbSNP: rs34319539

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000198941	SCV000254416	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-12-18	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with isoleucine, which is neutral and non-polar, at codon 909 of the MSH2 protein (p.Lys909Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with colorectal cancer (PMID: 15872200, 22581703). ClinVar contains an entry for this variant (Variation ID: 216359). 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 with a negative predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect MSH2 function (PMID: 22581703). 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	RCV000223226	SCV000278667	benign	Hereditary cancer-predisposing syndrome	2022-05-10	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx	RCV000235290	SCV000293241	uncertain significance	not provided	2023-03-20	criteria provided, single submitter	clinical testing	Published functional studies demonstrate no damaging effect (Kantelinen et al., 2012; Jia et al., 2020); Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Observed in an individual with colorectal cancer who also carried an MSH6 variant and whose tumor displayed microsatellite instability (MSI-H), absence of MLH1 protein and presence of MSH2 and MSH6 proteins by immunohistochemistry (IHC) (Hampel et al., 2005); This variant is associated with the following publications: (PMID: 19389263, 22581703, 22179786, 18822302, 21120944, 27873144, 9774676, 30267214, 15872200, 33357406)
Counsyl	RCV000412048	SCV000489431	uncertain significance	Lynch syndrome 1	2016-10-11	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000223226	SCV000690092	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-10	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with isoleucine at codon 909 of the MSH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown that this variant does not affect MSH2 mismatch repair activity in an in vitro mismatch repair efficiency assay (PMID: 22581703) and does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). This variant has been reported in individuals affected with colorectal cancer, with tumor samples showing microsatellite instability (PMID: 15872200, 22581703) and with one individual having normal MSH2 and MSH6 protein expression but lack of MLH1 protein expression via immunohistochemistry (PMID: 22581703). 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.
Myriad Genetics, Inc.	RCV000412048	SCV004018268	likely benign	Lynch syndrome 1	2023-03-17	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Baylor Genetics	RCV000412048	SCV004196826	uncertain significance	Lynch syndrome 1	2023-05-25	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997023	SCV004829931	uncertain significance	Lynch syndrome	2023-05-16	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with isoleucine at codon 909 of the MSH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown that this variant does not affect MSH2 mismatch repair activity in an in vitro mismatch repair efficiency assay (PMID: 22581703) and does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). This variant has been reported in individuals affected with colorectal cancer, with tumor samples showing microsatellite instability (PMID: 15872200, 22581703) and with one individual having normal MSH2 and MSH6 protein expression but lack of MLH1 protein expression via immunohistochemistry (PMID: 22581703). 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.