ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.663A>C (p.Glu221Asp) (rs41557217)

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Total submissions: 19
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000588752 SCV000149349 likely benign not provided 2021-04-16 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 27153395, 28767289, 17453009, 18269114, 24728327, 23621914, 26300997, 22290698, 21153778, 23047549, 26898890, 26333163, 17344846, 28531214, 28481244, 28874130, 29575718, 18301448, 31159747, 32854451)
Invitae RCV001083709 SCV000166237 benign Hereditary nonpolyposis colorectal neoplasms 2020-12-07 criteria provided, single submitter clinical testing
Ambry Genetics RCV000115440 SCV000185332 benign Hereditary cancer-predisposing syndrome 2014-07-01 criteria provided, single submitter clinical testing Internal frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance;Seen in trans with a mutation or in homozygous state in individual without severe disease for that gene
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000121575 SCV000604274 likely benign not specified 2016-12-02 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000588752 SCV000695925 benign not provided 2016-10-28 criteria provided, single submitter clinical testing Variant summary: The MSH6 c.663A>C (p.Glu221Asp) variant causes a missense change involving a non-conserved nucleotide with 5/5 in silico tools predict a benign outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 75/119664 (1/1595), which is approximately 4 times the estimated maximal expected allele frequency for a pathogenic MSH6 variant of 1/7037 (0.0001421), suggesting this variant is likely a benign polymorphism. The variant of interest has been reported in multiple affected individuals via publications. In addition, multiple clinical diagnostic laboratories/databases cite the variant as "likely benign/benign." Therefore, taking all available lines of evidence into consideration, the variant of interest has been classified as Benign.
Center for Human Genetics, Inc,Center for Human Genetics, Inc RCV000659887 SCV000781782 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2016-11-01 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000588752 SCV000805910 likely benign not provided 2017-10-12 criteria provided, single submitter clinical testing
GeneKor MSA RCV000115440 SCV000821800 likely benign Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Mendelics RCV000075021 SCV000837870 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000588752 SCV000889505 benign not provided 2018-08-15 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115440 SCV000902593 benign Hereditary cancer-predisposing syndrome 2016-04-11 criteria provided, single submitter clinical testing
Mendelics RCV000659887 SCV001135794 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000588752 SCV001152287 uncertain significance not provided 2018-06-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000659887 SCV001302617 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2019-05-01 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.
ITMI RCV000121575 SCV000085771 not provided not specified 2013-09-19 no assertion provided reference population
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353587 SCV000592573 likely benign Carcinoma of colon no assertion criteria provided clinical testing The MSH6 p.Glu221Asp variant was identified in 7 of 1567 proband chromosomes (frequency: 0.004) from individuals or families with colorectal cancer (Devlin 2008, Steinke 2008, Bodian 2014, Liccardo 2017, Overbeek 2007, Simbolo 2015). The variant was also identified in dbSNP (ID: rs41557217) as "With Uncertain significance, other allele ", ClinVar (classified as benign by Invitae, Ambry Genetics and one clinical laboratory; as likely benign by GeneDx and four clinical laboratories; as uncertain significance by tree submitters), COGR, Cosmic (1x in Haematopoietic and lymphoid tissue), MutDB, UMD-LSDB (3x as unclassified variant), Mismatch Repair Genes Variant Database (1x), and in Insight Hereditary Tumors Database (2x VUS). The variant was not identified in Zhejiang University Database. The variant was identified in control databases in 189 of 275098 chromosomes at a frequency of 0.0007 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: African in 6 of 23956 chromosomes (freq: 0.0003), Other in 3 of 6442 chromosomes (freq: 0.0005), Latino in 12 of 34380 chromosomes (freq: 0.0003), European in 133 of 126092 chromosomes (freq: 0.001), East Asian in 1 of 18824 chromosomes (freq: 0.00005), Finnish in 1 of 24524 chromosomes (freq: 0.00004), and South Asian in 33 of 30752 chromosomes (freq: 0.001), while the variant was not observed in the Ashkenazi Jewish population. The p.Glu221 residue is conserved in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. In addition, in functional assay using oligonucleotide-directed mutagenesis screen the variant was not identified as MMR abrogating; the variant was found in patients who also harbored a second, known pathogenic mutation in one of the DNA MMR genes that was likely causative for the LS phenotype (Houlleberghs 2017). The p.Glu221Asp was also detected in a second patient who was 83 years old and did not have a family history suspicious for LS. The observation of this variant with a co-occurring pathogenic variant (MLH1, EXON05-8, c.381-?_677del+?) by our laboratory increases the likelihood this variant does not have clinical significance. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Mayo Clinic Laboratories, Mayo Clinic RCV000121575 SCV000691920 uncertain significance not specified no assertion criteria provided clinical testing
True Health Diagnostics RCV000115440 SCV000788058 likely benign Hereditary cancer-predisposing syndrome 2017-08-30 no assertion criteria provided clinical testing
Medical Genetics Laboratory, Umraniye Training and Research Hospital,University of Health Sciences RCV001564013 SCV001786710 uncertain significance Abnormality of the ovary 2021-08-16 no assertion criteria provided clinical testing

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