Submissions for variant NM_000179.3(MSH6):c.3160A>T (p.Ile1054Phe)

gnomAD frequency: 0.00016  dbSNP: rs267608075

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000074806	SCV000108017	likely benign	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Multifactorial likelihood analysis posterior probability 0.001-0.049
GeneDx	RCV000586516	SCV000149312	likely benign	not provided	2020-09-08	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 23621914, 22645183, 22290698, 18301448, 23047549, 25479140)
Ambry Genetics	RCV000115403	SCV000172809	likely benign	Hereditary cancer-predisposing syndrome	2019-01-15	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	RCV001080837	SCV000218996	benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000200988	SCV000695841	benign	not specified	2021-07-16	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.3160A>T (p.Ile1054Phe) results in a non-conservative amino acid change located in the core domain (IPR007696) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 246296 control chromosomes (gnomAD). The observed variant frequency is slightly higher than the estimated maximal expected allele frequency for a pathogenic variant in MSH6 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (0.00014), suggesting that the variant can be benign. c.3160A>T has been reported in the literature in an individual affected with colon cancer (Steinke_2008), however, the microsatellite status was stable in the associated tumor, and the MSH6 protein expression was preserved. The variant was reported in individuals with other tumor phenotypes (e.g. Pal_2012, Grant_2014, Dorling_2021), but was also found in several controls (Dorling_2021). At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated that the relative repair efficiency of the p.I1054F variant protein was similar to the wild-type (Drost_2020). In addition, a recent multifactorial likelihood analysis that included allele frequency, co-occurrence, co-segregation, clinical and family history information as well as tumor characteristics, predicted this variant to be benign (Li_2020). Ten other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as benign (n=2), likely benign (n=7) or VUS (n=1). Based on the evidence outlined above, the variant was classified as benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000586516	SCV000889484	likely benign	not provided	2023-07-06	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115403	SCV000910609	benign	Hereditary cancer-predisposing syndrome	2015-12-09	criteria provided, single submitter	clinical testing
Mendelics	RCV000986730	SCV001135831	likely benign	Lynch syndrome 5	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000586516	SCV001152298	likely benign	not provided	2023-03-01	criteria provided, single submitter	clinical testing	MSH6: BS3:Supporting
Illumina Laboratory Services, Illumina	RCV000986730	SCV001302730	uncertain significance	Lynch syndrome 5	2017-04-27	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 of Human Genetics, University of Leipzig Medical Center	RCV001262329	SCV001440153	likely benign	Breast carcinoma	2019-01-01	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000200988	SCV002070929	uncertain significance	not specified	2019-01-28	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115403	SCV002535796	likely benign	Hereditary cancer-predisposing syndrome	2020-10-30	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000200988	SCV002552321	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149720	SCV003837648	likely benign	Breast and/or ovarian cancer	2021-08-03	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000115403	SCV004228157	likely benign	Hereditary cancer-predisposing syndrome	2023-10-17	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004537276	SCV004756733	likely benign	MSH6-related disorder	2019-11-15	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Mayo Clinic Laboratories, Mayo Clinic	RCV000586516	SCV000778622	likely benign	not provided	2017-11-10	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000074806	SCV001553951	likely benign	Lynch syndrome		no assertion criteria provided	clinical testing	The MSH6 p.Ile1054Phe variant was identified in 1 of 128 proband chromosomes (frequency: 0.008) from individuals or families with Lynch Syndrome (Steinke 2008). The variant was also identified in dbSNP (ID: rs267608075) as "With Uncertain significance allele ", ClinVar (classified as benign by Invitae; as likely benign by InSight, GeneDx, Mayo Clinic; as uncertain significance by Integrated Genetics/Laboratory Corporation of America), Cosmic (1x in breast tissue), Mismatch Repair Genes Variant Database, and in Insight Hereditary Tumors Database (1x). The variant was not identified in COGR, MutDB, UMD-LSDB, or Zhejiang University Database. The variant was identified in control databases in 46 of 272594 chromosomes at a frequency of 0.0002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 4 of 6410 chromosomes (freq: 0.0006), European in 18 of 125624 chromosomes (freq: 0.0001), Ashkenazi Jewish in 23 of 10110 chromosomes (freq: 0.002), and South Asian in 1 of 30758 chromosomes (freq: 0.00003), while the variant was not observed in the African, Latino, East Asian, or Finnish populations. The p.Ile1054 residue is conserved in mammals but not in more distantly related organisms however four out of five 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. 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, the variant demonstrated micro satellite stability and normal expression of MSH6 and prediction modeling determined the variant t be a polymorphism (Steinke 2008, Terui 2013). 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.