Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Color Diagnostics, |
RCV000581134 | SCV000684949 | uncertain significance | Hereditary cancer-predisposing syndrome | 2019-06-06 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001420714 | SCV000696218 | uncertain significance | not specified | 2021-05-10 | criteria provided, single submitter | clinical testing | Variant summary: MSH2 c.1593A>C (p.Lys531Asn) results in a non-conservative amino acid change located in the DNA mismatch repair protein Mut S, core domain (IPR007696) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251380 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1593A>C in individuals affected with Hereditary Nonpolyposis Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. |
| Prevention |
RCV000590460 | SCV000806003 | uncertain significance | not provided | 2017-11-29 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV000801092 | SCV000940850 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2024-04-17 | criteria provided, single submitter | clinical testing | This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 531 of the MSH2 protein (p.Lys531Asn). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MSH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 489919). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 333574060) indicates that this missense variant is not expected to disrupt MSH2 function with a negative predictive value of 80%. 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 | RCV000581134 | SCV002709712 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-04-25 | criteria provided, single submitter | clinical testing | The p.K531N variant (also known as c.1593A>C), located in coding exon 10 of the MSH2 gene, results from an A to C substitution at nucleotide position 1593. The lysine at codon 531 is replaced by asparagine, an amino acid with similar properties. 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. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Baylor Genetics | RCV004568265 | SCV005053474 | uncertain significance | Lynch syndrome 1 | 2024-01-30 | criteria provided, single submitter | clinical testing |