Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000759107 | SCV000888213 | likely pathogenic | not provided | 2018-01-10 | criteria provided, single submitter | clinical testing | |
| Myriad Genetics, |
RCV003452880 | SCV004186698 | likely pathogenic | Lynch syndrome 1 | 2023-08-07 | criteria provided, single submitter | clinical testing | This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 23690608]. This variant is expected to disrupt protein structure [Myriad internal data]. |
| Labcorp Genetics |
RCV003758687 | SCV004535300 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2023-10-28 | criteria provided, single submitter | clinical testing | This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 671 of the MSH2 protein (p.Asn671Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with MSH2-related conditions (PMID: 18383312, 30251116). ClinVar contains an entry for this variant (Variation ID: 90858). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33357406) indicates that this missense variant is expected to disrupt MSH2 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects MSH2 function (PMID: 23690608). 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 | RCV004019108 | SCV005033578 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2023-09-21 | criteria provided, single submitter | clinical testing | The p.N671K variant (also known as c.2013T>A), located in coding exon 13 of the MSH2 gene, results from a T to A substitution at nucleotide position 2013. The asparagine at codon 671 is replaced by lysine, an amino acid with similar properties. This alteration demonstrated deficient mismatch repair activity in a cellular-based functional assay using human/mouse expression systems (Drost M et al. Proc Natl Acad Sci U S A, 2013 Jun;110:9403-8). 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 deleterious (Jia X et al. Am J Hum Genet, 2021 Jan;108:163-175). This alteration was detected in an individual with MMR-deficient early-onset colon cancer amongst a cohort of 372 unrelated individuals undergoing genetic testing for Lynch syndrome (LS) based on a personal and/or family history of LS-associated cancers (Henriksson I et al. J Community Genet, 2019 Apr;10:259-266). This alteration was also identified in an individual diagnosed with colorectal cancer at 45 (Rohlin A et al. Fam Cancer, 2017 Apr;16:195-203). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. |