ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2354A>C (p.His785Pro) (rs200252727)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000165012 SCV000215707 likely benign Hereditary cancer-predisposing syndrome 2017-05-15 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: No disease association in small case-control study,Other data supporting benign classification
Invitae RCV000196615 SCV000254406 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-03 criteria provided, single submitter clinical testing This sequence change replaces histidine with proline at codon 785 of the MSH2 protein (p.His785Pro). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and proline. This variant is present in population databases (rs200252727, ExAC 0.003%). This variant has been reported in the literature in a patient affected with colorectal cancer (PMID: 25559809). ClinVar contains an entry for this variant (Variation ID: 185569). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
GeneDx RCV000587565 SCV000617593 uncertain significance not provided 2019-01-15 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.2354A>C at the cDNA level, p.His785Pro (H785P) at the protein level, and results in the change of a Histidine to a Proline (CAT>CCT). This variant has been identified in at least one individual with a personal and family history of colorectal cancer, co-occurring with a POLD1 variant (Chubb 2015). MSH2 His785Pro was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Histidine and Proline differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH2 His785Pro occurs at a position that is conserved across species and is located in the ATPase domain (Lützen 2008, Kansikas 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether MSH2 His785Pro is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000165012 SCV000685035 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-25 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000587565 SCV000696245 uncertain significance not provided 2016-03-07 criteria provided, single submitter clinical testing Variant summary: The MSH2 c.2354A>C variant affects a conserved nucleotide, resulting in amino acid change from His to Pro. 4/4 in-silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant is found in 2/121394 control chromosomes at a frequency of 0.0000165, which does not significantly exceed maximal expected frequency of a pathogenic allele (0.0005683). The variant has been reported in one CRC patient with a family history of CRC from the literature, however co-segregation data was not provided. In addition, multiple clinical laboratories classified this variant as uncertain significance. Because of the limited clinical data and the lack of functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000522265 SCV000712626 uncertain significance not specified 2016-11-17 criteria provided, single submitter clinical testing The p.His785Pro variant in MSH2 has been reported in 1 individual with colorecta l cancer; however, this patient also harbored a likely disease causing variant i n the POLD1 gene (Chubb et al 2015; POLD1, Ser478Asn: Palles 2013). The His785Pr o variant has been identified in 2/66730 European chromosomes by the Exome Aggre gation Consortium (ExAC,; dbSNP rs200252727). Com putational prediction tools and conservation analysis suggest that the p.His785P ro variant may impact the protein, though this information is not predictive eno ugh to determine pathogenicity. In summary, the clinical significance of the p.H is785Pro variant is uncertain.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000587565 SCV001134353 uncertain significance not provided 2019-08-26 criteria provided, single submitter clinical testing

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