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

gnomAD frequency: 0.00064  dbSNP: rs41557217

Total submissions: 23

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)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001083709	SCV000166237	benign	Hereditary nonpolyposis colorectal neoplasms	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000115440	SCV000185332	benign	Hereditary cancer-predisposing syndrome	2014-07-01	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
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	Lynch syndrome 5	2016-11-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	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
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000588752	SCV000889505	likely benign	not provided	2022-12-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115440	SCV000902593	benign	Hereditary cancer-predisposing syndrome	2016-04-11	criteria provided, single submitter	clinical testing
Mendelics	RCV003492405	SCV001135794	likely benign	Hereditary cancer	2024-01-23	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000588752	SCV001152287	likely benign	not provided	2024-05-01	criteria provided, single submitter	clinical testing	MSH6: BP1, BP4, BP5
Illumina Laboratory Services, Illumina	RCV000659887	SCV001302617	uncertain significance	Lynch syndrome 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.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000588752	SCV002010077	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798257	SCV002042061	likely benign	Breast and/or ovarian cancer	2023-05-17	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000121575	SCV002071573	likely benign	not specified	2021-01-15	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115440	SCV002536343	likely benign	Hereditary cancer-predisposing syndrome	2021-06-24	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000121575	SCV002552282	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
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