ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1019T>C (p.Phe340Ser) (rs61753793)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000160713 SCV000212731 likely benign Hereditary cancer-predisposing syndrome 2018-05-03 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Other data supporting benign classification
Color RCV000160713 SCV000685154 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-16 criteria provided, single submitter clinical testing
GeneDx RCV000656892 SCV000211345 uncertain significance not provided 2018-07-12 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.1019T>C at the cDNA level, p.Phe340Ser (F340S) at the protein level, and results in the change of a Phenylalanine to a Serine (TTC>TCC). This variant was observed in at least one individual diagnosed with colorectal cancer and multiple polyps at age 75 and was absent in 123 healthy controls (Plaschke 2000). Thompson et al. (2013) predicted this variant to be likely not pathogenic based on a combination of tumor characteristics and bioinformatic data. MSH6 Phe340Ser was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the Nuclear localization signal (Gassman 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether MSH6 Phe340Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000074626 SCV000107826 likely benign Lynch syndrome 2013-09-05 reviewed by expert panel research Multifactorial likelihood analysis posterior probability 0.001-0.049
Invitae RCV000524096 SCV000254269 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-04 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with serine at codon 340 of the MSH6 protein (p.Phe340Ser). The phenylalanine residue is moderately conserved and there is a large physicochemical difference between phenylalanine and serine. This variant is present in population databases (rs61753793, ExAC 0.009%). This variant has been reported in an individual affected with multiple primary cancers, including colorectal cancer (PMID: 10699937). ClinVar contains an entry for this variant (Variation ID: 89165). Gene-specific algorithms and a multifactorial likelihood analysis predict that this missense change is neutral or likely not pathogenic (PMID: 22949379, 22290698, 23621914). 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000212640 SCV000539711 uncertain significance not specified 2016-08-12 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ClinVar: Classified as LB by expert panel in 2013; 2 VUS (GeneDx and Invitae)

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