ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.1019T>C (p.Phe340Ser) (rs61753793)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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
GeneDx RCV000656892 SCV000211345 likely benign not provided 2021-04-07 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with colorectal and other cancers (Plaschke 2000); This variant is associated with the following publications: (PMID: 32926152, 22290698, 10699937, 22949379, 23621914, 11900875, 30212499, 32694065, 31965077)
Ambry Genetics RCV000160713 SCV000212731 likely benign Hereditary cancer-predisposing syndrome 2018-05-03 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other data supporting benign classification
Invitae RCV000524096 SCV000254269 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2020-10-29 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)
Color Health, Inc RCV000160713 SCV000685154 uncertain significance Hereditary cancer-predisposing syndrome 2020-09-30 criteria provided, single submitter clinical testing This missense variant replaces phenylalanine with serine at codon 340 of the MSH6 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with colorectal cancer, whose tumor showed low microsatellite instability and presence of mismatch repair proteins by immunohistochemistry (PMID: 10699937). This variant has been identified in 10/282726 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Mendelics RCV000986712 SCV001135800 benign Hereditary nonpolyposis colorectal cancer type 5 2019-05-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000986712 SCV001297400 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2017-04-28 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000212640 SCV001821249 uncertain significance not specified 2021-08-13 criteria provided, single submitter clinical testing Variant summary: MSH6 c.1019T>C (p.Phe340Ser) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. A MMR missense classifier tool called PON-MMR prediction method (pathogenic-or-not mismatch repair) classifies this variant as neutral (example, Ali_2012). The variant allele was found at a frequency of 3.6e-05 in 251320 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1019T>C has been reported in the literature in individuals affected with colorectal cancer and/or endometrial cancer (example, Plaschke_2000, Rosa_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Furthermore, a multifactorial probability based assessment reports this variant with a final classification of "Likely not Pathogenic" (IARC class 2) (Thompspon_2013). At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant in the complete in vitro MMR activity (CIMRA) assay (example, Dorst_2020). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (benign/likely benign, n=2; VUS, n=5). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.

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