Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV000166502 | SCV000217301 | uncertain significance | Hereditary cancer-predisposing syndrome | 2024-01-30 | criteria provided, single submitter | clinical testing | The p.G126S variant (also known as c.376G>A), located in coding exon 3 of the MSH2 gene, results from a G to A substitution at nucleotide position 376. The glycine at codon 126 is replaced by serine, an amino acid with similar properties. This alteration was detected in conjunction with a pathogenic MSH2 mutation (phase unknown) in an Italian individual meeting Amsterdam I criteria, whose tumor demonstrated microsatellite instability and loss of MSH2 protein expression (De Lellis L et al. PLoS ONE, 2013 Nov;8:e81194). This alteration has also been detected in a Hispanic patient diagnosed with a Lynch syndrome-associated cancer (Sunga AY et al. Cancer Genet. 2017 Apr;212-213:1-7). 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 (Jia X et al. Am J Hum Genet, 2021 01;108:163-175). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear. |
Invitae | RCV000199020 | SCV000254419 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2024-01-05 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 126 of the MSH2 protein (p.Gly126Ser). This variant is present in population databases (rs767371843, gnomAD 0.0009%). This missense change has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 24278394, 28449805). ClinVar contains an entry for this variant (Variation ID: 186849). 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%. 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. |
Fulgent Genetics, |
RCV000515190 | SCV000611401 | uncertain significance | Lynch syndrome 1; Mismatch repair cancer syndrome 1; Muir-Torré syndrome | 2017-05-23 | criteria provided, single submitter | clinical testing | |
Color Diagnostics, |
RCV000166502 | SCV001349879 | uncertain significance | Hereditary cancer-predisposing syndrome | 2019-06-27 | criteria provided, single submitter | clinical testing | |
All of Us Research Program, |
RCV003995507 | SCV004830098 | uncertain significance | Lynch syndrome | 2024-01-03 | criteria provided, single submitter | clinical testing |