Total submissions: 7
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV000130169 | SCV000185005 | benign | Hereditary cancer-predisposing syndrome | 2021-10-28 | 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. |
Invitae | RCV000198710 | SCV000254410 | likely benign | Hereditary nonpolyposis colorectal neoplasms | 2023-12-10 | criteria provided, single submitter | clinical testing | |
Gene |
RCV000520077 | SCV000616787 | uncertain significance | not provided | 2018-11-28 | criteria provided, single submitter | clinical testing | This variant is denoted MSH2 c.2503A>G at the cDNA level, p.Asn835Asp (N835D) at the protein level, and results in the change of an Asparagine to an Aspartic Acid (AAT>GAT). This variant was observed in at least two individuals with microsatellite unstable tumors, one with colon cancer who also harbored a second MSH2 missense variant, and another with endometrial cancer (Samowitz 2001, Hampel 2006). On functional interrogation, MSH2 Asn835Asp demonstrated mismatch repair proficiency in mouse embryonic stem cells (Houlleberghs 2016). This variant was not observed at a significant allele frequency in large population cohorts (Lek 2016). MSH2 Asn835Asp is located in the ATPase domain (Lutzen 2008, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether MSH2 Asn835Asp is pathogenic or benign. We consider it to be a variant of uncertain significance. |
Color Diagnostics, |
RCV000130169 | SCV000906780 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-10-19 | criteria provided, single submitter | clinical testing | This missense variant replaces asparagine with aspartic acid at codon 835 of the MSH2 protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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). This variant has been reported in an individual affected with colorectal cancer (PMID: 11606497). 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 also been identified in 1/251448 chromosomes 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. |
Sema4, |
RCV000130169 | SCV002534481 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-12-21 | criteria provided, single submitter | curation | |
Baylor Genetics | RCV003460914 | SCV004196269 | uncertain significance | Lynch syndrome 1 | 2023-09-06 | criteria provided, single submitter | clinical testing | |
All of Us Research Program, |
RCV003997554 | SCV004834238 | uncertain significance | Lynch syndrome | 2024-01-22 | criteria provided, single submitter | clinical testing | This missense variant replaces asparagine with aspartic acid at codon 835 of the MSH2 protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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). This variant has been reported in an individual affected with colorectal cancer (PMID: 11606497). 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 also been identified in 1/251448 chromosomes 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. |