Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| University of Washington Department of Laboratory Medicine, |
RCV002290960 | SCV000887336 | likely pathogenic | Hereditary nonpolyposis colon cancer | 2022-10-01 | criteria provided, single submitter | clinical testing | MSH2 NM_000251.2:c.518T>C has over 95% probability of pathogenicity based evidence of seeing this as a somatic mutation in a tumor with loss of heterozygosity at the MSH2 locus and again as a germline variant paired with a single heterozygous somatic MSH2 mutation in a separate tumor. See Shirts et al 2018, PMID 29887214. |
| Invitae | RCV001854331 | SCV002309538 | pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2023-07-07 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Leu173 amino acid residue in MSH2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17011982, 22290698, 28577310, 28874130). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects MSH2 function (PMID: 17101317, 18951462, 26951660). 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. ClinVar contains an entry for this variant (Variation ID: 91121). This missense change has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 15849733, 16395668, 17101317, 18383312, 23741719; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 173 of the MSH2 protein (p.Leu173Pro). |
| Ambry Genetics | RCV002336228 | SCV002643760 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2020-06-22 | criteria provided, single submitter | clinical testing | The p.L173P variant (also known as c.518T>C), located in coding exon 3 of the MSH2 gene, results from a T to C substitution at nucleotide position 518. The leucine at codon 173 is replaced by proline, an amino acid with similar properties. This alteration was reported in an individual whose colorectal tumor demonstrated high microsatellite instabilty (MSI-H) with loss of MSH2 protein expression on immunohistochemistry (IHC) and had a family history that met Amsterdam criteria for Lynch syndrome (Mangold E et al. Int. J. Cancer, 2005 Sep;116:692-702; Ollila S et al. Gastroenterology, 2006 Nov;131:1408-17). This alteration was also identified as a somatic variant in conjunction with loss of heterozygosity of MSH2 in a Lynch syndrome-related tumor demonstrating MMR deficiency by IHC (Shirts BH et al. Am. J. Hum. Genet., 2018 07;103:19-29). In an in vitro complementation assay using human nuclear extracts from a colorectal cell line, this alteration demonstrated reduced (less than 10%) mismatch repair (MMR) activity compared to wild type MSH2 (Ollila S et al. Gastroenterology, 2006 Nov;131:1408-17). In another functional study, this alteration showed resistance to a DNA damaging agent known to cause cell death in MMR-proficient cells, had reduced protein expression compared to wild type MSH2, and demonstrated microsatellite instability in a cellular assay using a slippage reporter (Houlleberghs H et al. Proc. Natl. Acad. Sci. U.S.A., 2016 Apr;113:4128-33). Furthermore, this alteration demonstrated no aberrant splicing in a functional assay using RT-PCR (Auclair J et al. Hum. Mutat., 2006 Feb;27:145-54). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. In addition, this alteration is predicted to be deleterious by MAPP-MMR in silico analysis (Chao EC et al. Hum. Mutat. 2008 Jun;29:852-60). Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| All of Us Research Program, |
RCV003997177 | SCV004822610 | likely pathogenic | Lynch syndrome | 2024-02-05 | criteria provided, single submitter | clinical testing | This missense variant replaces leucine with proline at codon 173 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). Functional studies have shown that this variant causes significantly decreased mismatch repair activity compared to wild type protein (PMID: 17101317, 17594722, 18951462), and that the variant impacts MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold >= 0.88, PMID: 33357406). This variant has been reported in individuals affected with Lynch syndrome (PMID: 15849733, 17101317, 17594722, 18951462, 33422027). A different variant affecting the same codon, c.518T>G (p.Leu173Arg), is considered to be disease-causing (ClinVar variation ID: 91122), suggesting that this position is important for the protein function. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. |
| Department of Pathology and Laboratory Medicine, |
RCV001353990 | SCV000592467 | likely pathogenic | Carcinoma of colon | no assertion criteria provided | clinical testing | The p.Leu173Pro variant has been reported in the literature in 16/3584 proband chromosomes (Auclair 2006, Chao 2008, Kansikas 2011, Mangold 2005, Ollila 2006, Ollila 2006b, Ollila 2008, Ou 2007) from patients who met either the Bethesda criteria or Amsterdam criteria II. However, no control chromosomes were tested to establish the frequency of the variant in the general population. It is listed in dbSNP database as coming from a "clinical source" (ID#: rs63750070), but no frequency information was provided, and so the prevalence of this variant in the population is not known. The p.Leu173 residue is conserved across mammals and computational analyses (PolyPhen, SIFT, AlignGVGD) suggest that the p.Leu173Pro variant may impact the protein. However, this information is not predictive enough to assume pathogenicity. Functional assays evaluating the stability and/or MMR activity of the variant reveal that compared to the wildtype allele, the variant exhibits reduced repair efficiency and is also less stable (Ollila 2006b, Kansikas 2011, Ollila 2008). In addition, HNPCC-associated tumors from carriers were MSI-H and MSH2 deficient by immunohistochemistry (Kansikas 2011, Mangold 2005, Ollila 2006b). In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time, although we would lean towards a more pathogenic role for this variant. This variant is classified as Predicted Pathogenic. |