ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2060T>C (p.Leu687Pro) (rs587779133)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000586744 SCV000211196 uncertain significance not provided 2017-03-08 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.2060T>C at the cDNA level, p.Leu687Pro (L687P) at the protein level, and results in the change of a Leucine to a Proline (CTC>CCC). This variant was observed in two tumors of the large intestine; however, it was not determined whether these variants were somatic or germline (COSMIC). MSH2 Leu687Pro was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Leucine and Proline differ in some properties, this is considered a semi-conservative amino acid substitution. MSH2 Leu687Pro occurs at a position that is highly conserved across species and is located in the ATPase domain (Lutzen 2008). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether MSH2 Leu687Pro is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000160600 SCV000212848 pathogenic Hereditary cancer-predisposing syndrome 2020-08-14 criteria provided, single submitter clinical testing The p.L687P pathogenic mutation (also known as c.2060T>C), located in coding exon 13 of the MSH2 gene, results from a T to C substitution at nucleotide position 2060. The leucine at codon 687 is replaced by proline, an amino acid with very few similar properties. In a cohort of patients from the UK, this alteration was reported in a patient suspected of having Lynch syndrome (Barrow E et al. Histopathology, 2010 Feb;56:331-44). In another study aimed at describing the characteristics of individuals with Lynch syndrome, this alteration was reported in two probands from a cohort undergoing multigene panel testing (Espenschied CR et al. J. Clin. Oncol., 2017 Aug;35:2568-2575). This alteration has been identified in multiple unrelated families meeting Amsterdam criteria for Lynch syndrome, one of which had co-segregation with disease in five family members (Ambry internal data). This alteration has also been identified in several probands whose Lynch syndrome-associated tumors demonstrated loss of MSH2 and/or MSH6 expression on immunohistochemistry (Ambry internal data). Based on an internal structural assessment using published crystal structures, this alteration results in destabilization of ATPase domain (Ambry internal data; Warren JJ et al. Mol. Cell, 2007 May;26:579-92). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae RCV000524374 SCV000548193 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2020-03-08 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 687 of the MSH2 protein (p.Leu687Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals and families affected with suspected or confirmed Lynch syndrome (PMID: 20459533, Invitae), and was observed to segregate with disease in a single family (Invitae). ClinVar contains an entry for this variant (Variation ID: 90873). An algorithm developed specifically for the MSH2 gene suggests that this missense change is likely to be deleterious (PMID: 22290698). However, this prediction has not been confirmed by published functional studies and its clinical significance is uncertain. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000586744 SCV000696233 uncertain significance not provided 2017-07-06 criteria provided, single submitter clinical testing Variant summary: The MSH2 c.2060T>C (p.Leu687Pro) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant is absent in 121380 control chromosomes and has been reported in affected individuals in the literature, without strong evidence for causality as evidenced by absence of co-segregation information, lack of MSI data, and positive staining on IHC analysis (Barrow_Hist_2010). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS until additional evidence becomes available.
Color Health, Inc RCV000160600 SCV001344423 likely pathogenic Hereditary cancer-predisposing syndrome 2019-11-20 criteria provided, single submitter clinical testing

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