ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1109T>C (p.Leu370Ser) (rs587779204)

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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 RCV000162441 SCV000212790 likely pathogenic Hereditary cancer-predisposing syndrome 2019-08-05 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Good segregation with disease (lod 1.5-3 = 5-9 meioses);In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Rarity in general population databases (dbsnp, esp, 1000 genomes);Other data supporting pathogenic classification;Moderate segregation with disease (at least 3 informative meioses) for rare diseases.
Invitae RCV000524101 SCV000261301 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-10-16 criteria provided, single submitter clinical testing This sequence change replaces leucine with serine at codon 370 of the MSH6 protein (p.Leu370Ser). The leucine residue is moderately conserved and there is a large physicochemical difference between leucine and serine. This variant is not present in population databases (rs587779204, ExAC no frequency). This variant has been observed in several individuals affected with endometrial cancer and/or colorectal cancer (PMID: 24933100, 24244552, Invitae). Moreover, it has been observed to segregate with Lynch syndrome related cancers in one family (PMID: 27978560). ClinVar contains an entry for this variant (Variation ID: 89172). An algorithm developed specifically for the MSH6 gene suggests that this missense change is likely to be deleterious (PMID: 23621914). 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.
GeneDx RCV000518839 SCV000568050 likely pathogenic not provided 2018-06-11 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.1109T>C at the cDNA level, p.Leu370Ser (L370S) at the protein level, and results in the change of a Leucine to a Serine (TTA>TCA). MSH6 Leu370Ser has been reported in at least two patients with endometrial cancer, one of whose tumor demonstrated absence of MSH6 on immunohistochemistry (Egoavil 2013, Batte 2014). This variant was also identified in an individual with colorectal cancer, whose tumor studies demonstrated mismatch repair deficiency via immunohistochemistry (IHC) and/or microsatellite instability; and the variant also demonstrated extensive co-segregation among the proband and affected family members (Pearlman 2017). MSH6 Leu370Ser was not observed in large population cohorts (Lek 2016). This variant is located in the mismatch binding domain and nuclear localization signal region (Warren 2007, Gassman 2011, Kansikas, 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, we consider MSH6 Leu370Ser to be a likely pathogenic variant.
University of Washington Department of Laboratory Medicine, University of Washington RCV000074633 SCV000579493 pathogenic Lynch syndrome 2016-05-17 criteria provided, single submitter clinical testing Co-segregation likelihood ratio >250, shared with 3th cousin with loss of MSH6 and others with Lynch cancers in large pedigree, likelihood ration for cosegregation >250
Color RCV000162441 SCV000685164 likely pathogenic Hereditary cancer-predisposing syndrome 2020-03-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001201190 SCV001372259 likely pathogenic Hereditary nonpolyposis colon cancer 2020-06-22 criteria provided, single submitter clinical testing Variant summary: MSH6 c.1109T>C (p.Leu370Ser) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. A bioinformatic tool to predict impact of missense variants in MSH6 has reported a damaging impact for this variant (Terui_2013). The variant was absent in 250994 control chromosomes. c.1109T>C has been reported in the literature in individuals affected with Lynch Syndrome/colorectal cancer (example, Batte_2014, Egoavil_2013, Pearlman_2017). At-least two of these reports demonstrated a loss of MSH6 expression in tumors by IHC analysis (Egoavil_2013, Pearlman_2017) and one of these reports demonstrated co-segregation with disease among two first and second generation relatives within the family (Pearlman_2017). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (pathogenic, n=1, likely pathogenic, n=3, VUS, n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000202023 SCV000257204 uncertain significance not specified no assertion criteria provided research

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