Submissions for variant NM_000179.3(MSH6):c.3245C>T (p.Pro1082Leu)

gnomAD frequency: 0.00010  dbSNP: rs191109849

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000656898	SCV000149318	likely benign	not provided	2021-05-07	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 23621914, 24072394, 24728327, 22290698, 25503501, 27498913, 29368341)
Ambry Genetics	RCV000115409	SCV000185751	likely benign	Hereditary cancer-predisposing syndrome	2018-09-28	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001085899	SCV000254309	likely benign	Hereditary nonpolyposis colorectal neoplasms	2025-02-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115409	SCV000537600	likely benign	Hereditary cancer-predisposing syndrome	2020-03-17	criteria provided, single submitter	clinical testing
Mendelics	RCV005234964	SCV000837911	likely benign	Hereditary cancer	2025-02-27	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following: it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease, and/or has normal protein function, and/or has lack of segregation with disease, and/or has been detected in co-occurrence with known pathogenic variant, and/or has lack of disease association in case-control studies, and/or is located in a region inconsistent with a known cause of pathogenicity.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000121583	SCV000919724	benign	not specified	2020-11-06	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.3245C>T (p.Pro1082Leu) 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 0.00034 in 252712 control chromosomes, predominantly at a frequency of 0.0014 within the Latino subpopulation in the gnomAD database, v2.1 exomes dataset. In addition, the variant was reported in Latino control individuals in the gnomAD database, v3.1 genomes dataset with an even higher frequency (i.e. 0.0038), including 2 homozygotes. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 10 to 30-fold higher than 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. c.3245C>T has been reported in the literature in individuals affected with (suspected) Lynch syndrome, and breast-, ovarian- or prostate cancer (Zahary_2014, Maxwell_2015, Kalady_2015, Isaaccon Velho_2018, Xiao_2020, Choi_2020). These data do not allow any conclusion about variant significance. Co-occurrences with other pathogenic variants have been reported (BRCA1 c.45delT (p.Asn16MetfsX7) and BARD1 c.55G>T ( p.Glu19X), both pathogenic variants have been reported in one specimen tested at our laboratory; and MLH1 c.345_349delTACAA (p.Thr116Glufs*4) in Xiao_2020; and BRCA1 c.3020delC (p.Ser1007*) in Choi_2020), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight other 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 (i.e. 4 calling it likely benign, and 4 classifying it as a VUS). Based on the evidence outlined above, the variant was classified as benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000656898	SCV001134425	benign	not provided	2022-10-09	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000656898	SCV001713987	uncertain significance	not provided	2019-11-03	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000656898	SCV002010096	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000121583	SCV002552332	benign	not specified	2025-03-04	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV002288561	SCV002579069	uncertain significance	Lynch syndrome 5	2022-06-08	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000656898	SCV003799813	likely benign	not provided	2022-04-07	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000074824	SCV005429399	likely benign	Lynch syndrome	2024-09-11	criteria provided, single submitter	clinical testing
ITMI	RCV000121583	SCV000085779	not provided	not specified	2013-09-19	no assertion provided	reference population
PreventionGenetics, part of Exact Sciences	RCV004528272	SCV000805884	likely benign	MSH6-related disorder	2023-10-09	no assertion criteria provided	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).
Ding PR Lab, Sun Yat-sen University Cancer Center	RCV001093655	SCV001250835	uncertain significance	Lynch syndrome 1		no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358430	SCV001554159	uncertain significance	Carcinoma of colon		no assertion criteria provided	clinical testing	The MSH6 p.Pro1082Leu variant was identified in 1 of 526 proband chromosomes (frequency: 0.002) from individuals or families with Lynch syndrome (Kalady 2015). The variant was also identified in dbSNP (ID: rs191109849) as with uncertain significance allele; in the ClinVar and Clinvitae databases as uncertain significance by InSiGHT, Gene Dx, Ambry Genetics, Color Genomics and as likely benign by Invitae. Furthermore, the variant was identified 1X in the Cosmic database and categorized as pathogenic with a FATHMM prediction score of 0.96, with the liver being the primary tissue of origin. The variant was also listed in the Insight Colon Cancer Gene Variant and Insight Hereditary Tumors Databases 2X as class 3. The variant was not identified in the GeneInsight-COGR, MutDB, UMD-LSDB, Zhejiang University, and the Mismatch Repair Genes Variant databases. The variant was identified in the 1000 Genomes Project in 2 of 5000 chromosomes (frequency: 0.0004) and in the NHLBI GO Exome Sequencing Project in 1 of 8600 European American alleles. The variant was identified in control databases in 85 of 277152 chromosomes at a frequency of 0.0003 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 2 of 24032 chromosomes (freq: 0.00008), Other in 5 of 6462 chromosomes (freq: 0.000774), Latino in 52 of 34400 chromosomes (freq: 0.001), European Non-Finnish in 16 of 126676 chromosomes (freq: 0.0001), East Asian in 6 of 18860 chromosomes (freq: 0.0003), European Finnish in 1 of 25790 chromosomes (freq: 0.00004), and South Asian in 3 of 30782 chromosomes (freq: 0.0001), while the variant was not observed in the Ashkenazi Jewish, populations. In one study, 616 MMR missense variants for Lynch syndrome patients were downloaded (January 27, 2011) from the International Society for Gastrointestinal Hereditary Tumours (In-SiGHT) database. The purpose was to develop a new consensus predictor to identify variants that are highly likely to be pathogenic, neutral, or of unknown pathogenicity status, this was subsequently applied to the 616 MMR cases and the p.Pro1082Leu variant was assigned a neutral category (Ali 2012). The p.Pro1082 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, 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 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.
Genetic Services Laboratory, University of Chicago	RCV000121583	SCV003839747	likely benign	not specified	2022-06-06	no assertion criteria provided	clinical testing