ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3260C>A (p.Pro1087His) (rs63750753)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000589544 SCV000149319 uncertain significance not provided 2019-01-15 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.3260C>A at the cDNA level, p.Pro1087His (P1087H) at the protein level, and results in the change of a Proline to a Histidine (CCC>CAC). This variant was identified in three patients, one each with breast cancer, gastric cancer, and acute myeloid leukemia, as well as in an individual diagnosed with an endometrial cancer that demonstrated absence of the MSH2 and MSH6 proteins by immunohistochemistry (Lu 2015, Rubio 2016). MSH6 Pro1087His was also identified in 1/62 healthy East Asian individuals undergoing whole genome sequencing (Bodian 2014). Of note, the participants in this study were younger than 50 years old thus the unaffected status of this individual may not be significant. MSH6 Pro1087His was observed at an allele frequency of 0.05% (17/34,400) in individuals of Latino ancestry in large population cohorts (Lek 2016). MSH6 Pro1087His is located in the ATPase domain (Warren 2007, Kansikas 2011). In-silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MSH6 Pro1087His is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115410 SCV000184771 uncertain significance Hereditary cancer-predisposing syndrome 2018-11-27 criteria provided, single submitter clinical testing Conflicting evidence
Invitae RCV000168382 SCV000219073 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-31 criteria provided, single submitter clinical testing This sequence change replaces proline with histidine at codon 1087 of the MSH6 protein (p.Pro1087His). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and histidine. This variant is present in population databases (rs63750753, ExAC 0.06%). This variant has been reported in an individual affected with endometrial cancer (PMID: 27398995), as well as individuals affected with breast cancer, gastric cancer, and acute myeloid leukemia (PMID: 26689913). ClinVar contains an entry for this variant (Variation ID: 127584) Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD), and an algorithm developed specifically for the MSH6 gene (PMID: 23621914), suggest that this missense change is likely to be disruptive. However, these predictions have not been confirmed by published functional studies. 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 RCV000115410 SCV000537572 uncertain significance Hereditary cancer-predisposing syndrome 2020-03-03 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000589544 SCV000601568 uncertain significance not provided 2019-06-05 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000121584 SCV000695851 uncertain significance not specified 2019-01-07 criteria provided, single submitter clinical testing Variant summary: The variant, MSH6 c.3260C>A (p.Pro1087His) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, core domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 278546 control chromosomes, predominantly at a frequency of 0.00049 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 3.5-fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH6 causing Lynch Syndrome phenotype (0.00014), suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. The variant, c.3260C>A, has been reported in the literature in individuals affected with breast cancer, ovarian cancer, endometrial cancer and Lynch Syndrome (Lu_2015, Kanchi_2014, Rubio_2016, Patel_2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign, until more functional and clinical data become available.
PreventionGenetics,PreventionGenetics RCV000589544 SCV000805886 uncertain significance not provided 2017-10-23 criteria provided, single submitter clinical testing
ITMI RCV000121584 SCV000085780 not provided not specified 2013-09-19 no assertion provided reference population
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000121584 SCV000691937 uncertain significance not specified no assertion criteria provided clinical testing

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