Submissions for variant NM_000179.3(MSH6):c.884A>G (p.Lys295Arg)

gnomAD frequency: 0.00014  dbSNP: rs267608051

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000512927	SCV000149354	likely benign	not provided	2021-03-08	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 21437237, 18566915, 23621914, 16010685, 26333163, 26689913, 23047549, 26845104)
Ambry Genetics	RCV000115445	SCV000214730	likely benign	Hereditary cancer-predisposing syndrome	2019-06-17	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	RCV000524217	SCV000254335	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-28	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000075042	SCV000266213	uncertain significance	Lynch syndrome	2015-11-20	criteria provided, single submitter	clinical testing
Counsyl	RCV000410872	SCV000487810	uncertain significance	Lynch syndrome 5	2015-11-18	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000212636	SCV000539701	uncertain significance	not specified	2016-03-28	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: 1 paper, no segs, ExAC: 0.02% (12/66598) European chromosomes
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000512927	SCV000601619	uncertain significance	not provided	2022-07-28	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.00018 (23/129030 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with colorectal cancer (PMID: 16010685 (2005)), 18566915 (2009), and 26845104 (2016)) and ovarian cancer (PMID: 23047549 (2012)). The variant was also reported in a large breast cancer study in both cases and controls (PMID: 33471991 (2021), https://databases.lovd.nl/shared/variants/MSH6/). This variant was reported to have no effect on MSH6 nuclear localization, however further studies are required to determine the global effect of this variant MSH6 protein function (PMID: 21437237 (2011)). 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. Based on the available information, we are unable to determine the clinical significance of this variant.
CeGaT Center for Human Genetics Tuebingen	RCV000512927	SCV000608936	uncertain significance	not provided	2017-05-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000212636	SCV000695929	likely benign	not specified	2022-08-19	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.884A>G (p.Lys295Arg) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.2e-05 in 251246 control chromosomes, predominantly at a frequency of 0.00019 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.34 fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH6 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (0.00014), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.884A>G has been reported in the literature associated with several types of cancer including but not limited to colorectal adenomas, Lynch syndrome, breast/ovarian cancer, colon cancer (Example: Lu_2015, Shirts_2015, Pal_2012, Nilbert_2009, Colley_2005, VanMarcke_2020). These reports however, do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. In one ovarian cancer patient, a pathogenic BRCA2 variant was also found in the patient, providing supporting evidence for a benign role (Li_2019). One study reports that this variant did not affect MSH6 cellular localization but its proficiency in mismatch repair activity has not been addressed (Gassman_2011). 12 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Nine submitters classified the variant as VUS while three classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Color Diagnostics, LLC DBA Color Health	RCV000115445	SCV000910671	likely benign	Hereditary cancer-predisposing syndrome	2014-12-09	criteria provided, single submitter	clinical testing
Mendelics	RCV000410872	SCV001135797	uncertain significance	Lynch syndrome 5	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000410872	SCV001302619	uncertain significance	Lynch syndrome 5	2018-08-16	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.
Sema4, Sema4	RCV000115445	SCV002536365	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-07	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000212636	SCV002552286	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000410872	SCV004018953	likely benign	Lynch syndrome 5	2023-03-29	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000512927	SCV001552237	uncertain significance	not provided		no assertion criteria provided	clinical testing	The MSH6 p.Lys295Arg variant was identified in 4 of 8180 proband chromosomes (frequency: 0.0005) from individuals or families with breast or colorectal cancer (Colley 2005, Nilbert 2009, Pal 2012, Shirts 2015). The variant was also identified in dbSNP (ID: rs267608051) as "With Uncertain significance allele ", ClinVar (classified as uncertain significance by InSight, GeneDx, Ambry Genetics, Invitae, Counsyl and five clinical laboratories), UMD-LSDB (2x as unclassified variant), Mismatch Repair Genes Variant Database, and in Insight Hereditary Tumors (2x) databases. The variant was not identified in GeneInsight-COGR, Cosmic, MutDB, or Zhejiang University, databases. The variant was identified in control databases in 26 of 276994 chromosomes at a frequency of 0.00009 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Latino in 1 of 34408 chromosomes (freq: 0.00003), European in 23 of 126552 chromosomes (freq: 0.0002), Finnish in 2 of 25790 chromosomes (freq: 0.00008), while the variant was not observed in the African, Other, Ashkenazi Jewish, East Asian, and South Asian populations. The p.Lys295 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In addition, in vitro study has shown that variant located in substantial amino-terminal region and does not disrupt MSH6 stability and localization signal. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.