Total submissions: 6
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV000204877 | SCV000260250 | likely benign | Hereditary nonpolyposis colorectal neoplasms | 2023-11-24 | criteria provided, single submitter | clinical testing | |
Ambry Genetics | RCV000491044 | SCV000580534 | likely benign | Hereditary cancer-predisposing syndrome | 2022-02-08 | criteria provided, single submitter | clinical testing | This alteration is classified as likely 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. |
Color Diagnostics, |
RCV000491044 | SCV000685053 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-09-19 | criteria provided, single submitter | clinical testing | This missense variant replaces alanine with serine at codon 848 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). A functional study suggests that the variant protein has in vitro DNA mismatch repair activity similar to the wild-type protein (PMID: 19697156). The 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 individuals affected with colorectal cancer (PMID: 18547406, 19697156), ovarian cancer (PMID: 23047549), and kidney cancer (PMID: 29684080). This variant has also been identified in 3/282842 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. |
Gene |
RCV001570632 | SCV001794960 | uncertain significance | not provided | 2023-03-21 | 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; Published functional studies demonstrate no damaging effect: intact mismatch repair activity and resistance to 6-TG similar to wild type (Christensen et al., 2009; Jia et al., 2020); Identified in individuals with colorectal, breast, ovarian, or renal cancer (Christensen et al., 2009; Pal et al., 2012; Yehia et al., 2018; Dorling et al., 2021); This variant is associated with the following publications: (PMID: 18547406, 29684080, 22290698, 23047549, 18822302, 21120944, 33471991, 19697156, 33357406) |
Sema4, |
RCV000491044 | SCV002534486 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-03-10 | criteria provided, single submitter | curation | |
All of Us Research Program, |
RCV003997603 | SCV004826420 | uncertain significance | Lynch syndrome | 2023-07-10 | criteria provided, single submitter | clinical testing | This missense variant replaces alanine with serine at codon 848 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). A functional study suggests that the variant protein has in vitro DNA mismatch repair activity similar to the wild-type protein (PMID: 19697156). The 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 individuals affected with colorectal cancer (PMID: 18547406, 19697156), ovarian cancer (PMID: 23047549), and kidney cancer (PMID: 29684080). This variant has also been identified in 3/282842 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. |