ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.559C>T (p.Leu187Phe) (rs759603999)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000574683 SCV000669757 uncertain significance Hereditary cancer-predisposing syndrome 2016-02-11 criteria provided, single submitter clinical testing <span style="font-size:12px"><span style="font-family:arial,helvetica,sans-serif">The p.L187F variant (also known as c.559C>T), located in coding exon 3 of the MSH2 gene, results from a C to T substitution at nucleotide position 559. The leucine at codon 187 is replaced by phenylalanine, an amino acid with highly similar properties. Although this exact alteration has not been described in the literature, two other mutations, p.L187R and p.L187P, have been described in the samecodon. Bothvariants have been identified in several individuals with early-onset CRCwhose families met Amsterdam criteria. Tumor results for these individuals also showedmicrosatellite instability and loss of both MSH2 and MSH6 on immunohistochemistry(Christensen LL et al., Fam. Cancer 2009; 8(4):489-500;Peel DJ et al., J.Natl. CancerInst. 2000 Sep; 92(18):1517-22;OllilaS et al., Int. J.Oncol. 2006 Jan; 28(1):149-53). Furthermore, functional assays measuring mismatch repair efficiencies for these variantshave shown significantdeficiencies in repair activity (ChristensenLL et al.,Fam. Cancer2009;OllilaS et al.,Int. J.Oncol.2006 Jan; 28(1):149-53).This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 115000alleles tested) in our clinical cohort.<span style="font-size:12px"><span style="font-family:arial,helvetica,sans-serif">This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive.In addition, this alteration is predicted to be borderline deleteriousbyMAPP-MMRinsilicoanalysis(Chao E et al.HumMutat. 2008Jun;29(6):852-60).Since supporting evidence is limited at this time, the clinical significance of p.L187F remains unclear.
Invitae RCV000810913 SCV000951153 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2018-08-12 criteria provided, single submitter clinical testing This sequence change replaces leucine with phenylalanine at codon 187 of the MSH2 protein (p.Leu187Phe). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MSH2-related disease. ClinVar contains an entry for this variant (Variation ID: 483679). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). Variants that disrupt the p.Leu187 amino acid residue in MSH2 have been observed in affected individuals (PMID: 18951462, 16327991, 28422960, 17101317, 26951660, 19697156). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. 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.
Color RCV000574683 SCV001348581 uncertain significance Hereditary cancer-predisposing syndrome 2020-01-17 criteria provided, single submitter clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.