ClinVar Miner

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

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Total submissions: 8
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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 2020-04-06 criteria provided, single submitter clinical testing The p.L370S variant (also known as c.1109T>C), located in coding exon 4 of the MSH6 gene, results from a T to C substitution at nucleotide position 1109. The leucine at codon 370 is replaced by serine, an amino acid with dissimilar properties. This alteration was found to co-segregate with disease in a large Amsterdam II family and the tumor of the index case was reported to be mismatch repair deficient (Ambry internal data; Pearlman R et al. JAMA Oncol. 2017 Apr;3:464-471). This alteration was detected in 1/173 unselected Spanish women with endometrial cancer and tumor studies for this individual showed microsatellite stability (MSS) with loss of MSH6 protein expression, but intact MSH2 protein expression (Egoavil C et al. PLoS One. 2013 Nov 7;8(11):e79737). This alteration was also detected in a 53-year-old woman whose endometrial cancer showed low microsatellite instability (MSI-L) with normal protein expression for all the mismatch repair proteins and she had no reported family history of colon or endometrial cancer (Batte BA et al. Gynecol Oncol. 2014 Aug;134(2):319-25). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae RCV000524101 SCV000261301 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2020-10-06 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 2021-03-16 criteria provided, single submitter clinical testing Observed in patients with Lynch-related cancers and tumor studies consistent with pathogenic variants in this gene (Egoavil 2013, Batte 2014, Pearlman 2017, Ranola 2018, Chen 2020, Hampel 2021); Not observed in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32719484, 17531815, 21120944, 24244552, 24933100, 27978560, 30019097, 32652087, 33393477, 30695780, 23621914, 26333163)
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 Health, Inc RCV000162441 SCV000685164 likely pathogenic Hereditary cancer-predisposing syndrome 2020-03-31 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000074633 SCV001653079 likely pathogenic Lynch syndrome 2020-02-10 criteria provided, single submitter clinical testing The p.Leu370Ser variant in MSH6 has been identified in at least 14 individuals with Lynch syndrome associated cancers and segregated with disease in 4 affected relatives from 2 families (Egoavil 2013, Batte 2014, Pearlman 2017, GeneDx pers. comm., Ambry pers. comm.). In addition, tumors sampled from at least 10 individuals lacked MSH6 expression and/or showed high microsatellite instability, while at least one tumor showed normal MSH6 expression and/or low microsatellite instability. This variant has also been reported by other clinical laboratories in ClinVar (Variation ID #89172) and was absent from large population studies. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP Criteria applied: PS4, PM2, PP1.
Mayo Clinic Laboratories, Mayo Clinic RCV000202023 SCV000257204 uncertain significance not specified no assertion criteria provided research

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