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

gnomAD frequency: 0.00006  dbSNP: rs61753793

Total submissions: 11

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	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Invitae	RCV000524096	SCV000254269	likely benign	Hereditary nonpolyposis colorectal neoplasms	2023-11-28	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham 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 Diagnostics, LLC DBA Color Health	RCV000160713	SCV000685154	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-13	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). An in vitro mismatch repair assay found normal activity (PMID: 31965077). This variant has been reported in an individual affected with colorectal cancer whose tumor showed low microsatellite instability and normal MSH6 immunohistochemistry (PMID: 10699937), and in an individual affected with colorectal cancer with high microsatellite instability and normal MSH6 immunohistochemistry (PMID: 29596542). This variant has also been reported in an individual affected with endometrial cancer and abnormal MSH6 immunohistochemistry (PMID: 32694065). 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	Lynch syndrome 5	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000986712	SCV001297400	uncertain significance	Lynch syndrome 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	2022-08-04	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). Nine 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=3; VUS, n=6). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000656892	SCV002046206	uncertain significance	not provided	2020-12-17	criteria provided, single submitter	clinical testing	This variant has been assessed to have no effect on mismatch repair activity using an invitro mismatch repair activity assay (PMID: 31965077 (2020)). Several bioinformatic prediction algorithms have classified this variant as a neutral or likely not pathogenic variant (PMID 22290698 (2012), 23621914 (2013), 22949379 (2013)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Taking into account the available information, we are unable to determine the clinical significance of this variant.
Sema4, Sema4	RCV000160713	SCV002535582	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-17	criteria provided, single submitter	curation