Submissions for variant NM_000179.3(MSH6):c.3217C>T (p.Pro1073Ser)

gnomAD frequency: 0.00028  dbSNP: rs142254875

Total submissions: 24

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000074820	SCV000108031	likely benign	Lynch syndrome	2018-10-18	reviewed by expert panel	curation	Multifactorial likelihood analysis posterior probability 0.001-0.049 (0.02)
GeneDx	RCV000034498	SCV000149315	likely benign	not provided	2020-07-31	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 32547938, 25741868, 28767289, 23621914, 26898890, 27153395, 22703879, 18269114, 22495361, 22290698, 23047549)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001084149	SCV000166227	benign	Hereditary nonpolyposis colorectal neoplasms	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000115406	SCV000187203	benign	Hereditary cancer-predisposing syndrome	2018-09-28	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.
CeGaT Center for Human Genetics Tuebingen	RCV000034498	SCV000493608	likely benign	not provided	2024-03-01	criteria provided, single submitter	clinical testing	MSH6: BS1:Supporting, BS2
Genetic Services Laboratory, University of Chicago	RCV000202106	SCV000595855	likely benign	not specified	2021-04-24	criteria provided, single submitter	clinical testing
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000659894	SCV000781791	uncertain significance	Lynch syndrome 5	2016-11-01	criteria provided, single submitter	clinical testing
Mendelics	RCV003323280	SCV000837910	benign	Hereditary nonpolyposis colon cancer	2023-08-22	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000074820	SCV000887451	uncertain significance	Lynch syndrome	2018-05-01	criteria provided, single submitter	clinical testing	MSH6 NM_000179.2:c.3217C>T has a 74.5% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 26.5 to 1, generated from evidence of seeing this as a somatic mutation in a tumor with loss of heterozygosity at the MSH6 locus. See Shirts et al 2018, PMID 29887214.
Fulgent Genetics, Fulgent Genetics	RCV000764428	SCV000895485	uncertain significance	Endometrial carcinoma; Mismatch repair cancer syndrome 1; Lynch syndrome 5	2018-10-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115406	SCV000910560	benign	Hereditary cancer-predisposing syndrome	2015-11-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000202106	SCV000919760	benign	not specified	2021-01-30	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.3217C>T (p.Pro1073Ser) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, 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 0.00045 in 251352 control chromosomes, predominantly at a frequency of 0.00023 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 1.6 fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH6 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (0.00014). Furthermore, the observed variant frequency within Ashkenazi Jewish control individuals in the gnomAD database is approximately 54 fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH6 causing Lynch Syndrome phenotype (0.00014). These observations strongly suggest that the variant is benign. c.3217C>T has been reported in the literature in individuals affected with features of HNPCC/Colorectal Cancer (example, Devlin_2008, Okkels_2012, Haraldsdottir_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer (Lynch syndrome). The UMD database reports its presence in individuals with microsatellite stable, IHC positive, sporadic colorectal cancer. A recent study reporting tumor characteristic likelihood ratio (TCLR) in combination with in silico predictors and a multifactorial variant prediction model that included allele frequency, co-occurrence, co-segregation, clinical and family history information, classified this variant as unequivocally benign (Li_2020). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Twelve 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 (likely benign/benign, n=5; VUS, n=7). Based on the evidence outlined above, the variant was classified as benign.
Illumina Laboratory Services, Illumina	RCV000659894	SCV001302732	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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Baylor Genetics	RCV000659894	SCV001525812	uncertain significance	Lynch syndrome 5	2018-03-22	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000034498	SCV002010097	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798060	SCV002042045	likely benign	Breast and/or ovarian cancer	2023-05-17	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115406	SCV002535803	benign	Hereditary cancer-predisposing syndrome	2020-09-21	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000202106	SCV002552327	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000034498	SCV002773912	benign	not provided	2022-08-02	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000115406	SCV005415611	likely benign	Hereditary cancer-predisposing syndrome	2024-11-05	criteria provided, single submitter	clinical testing	The missense variant NM_000179.3(MSH6):c.3217C>T (p.Pro1073Ser) has been reported to ClinVar as Likely benign with a status of (3 stars) reviewed by expert panel (Variation ID 41593 as of 2024-10-03). The p.Pro1073Ser variant is observed in 78/10,078 (0.774%) alleles from individuals of gnomAD Ashkenazi Jewish background in gnomAD, which is greater than expected for the disorder. There is a moderate physicochemical difference between proline and serine. For these reasons, this variant has been classified as Likely Benign.
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034498	SCV000043361	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.
Mayo Clinic Laboratories, Mayo Clinic	RCV000202106	SCV000257242	uncertain significance	not specified		no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV004528158	SCV000805883	likely benign	MSH6-related disorder	2021-02-12	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).
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358558	SCV001554328	uncertain significance	Carcinoma of colon		no assertion criteria provided	clinical testing	The MSH6 p.Pro1073Ser variant was identified in 4 of 6780 proband chromosomes (frequency: 0.0006) from individuals or families with Lynch syndrome, ovarian cancer, and colorectal cancer (Okkels 2012, Pal 2012, Haraldsdottir 2017). The variant was also identified in dbSNP (ID: rs142254875) as “With Uncertain significance allele”, in ClinVar (10x as Uncertain Significance by InSiGHT, GeneDx, University of Chicago, Biesecker Lab, Mayo Clinic and Praxis fuer Humangenetik, as Likely Benign by Ambry and as Benign by Invitae), UMD-LSDB (5x and classified as unknown), Mismatch Repair Genes Variant Database (1x), and the Insight Hereditary Tumors Database (1x). The variant was not identified in Cosmic, MutDB, Insight Colon Cancer Gene Variant Database, Zhejiang University Database, or the MMR Gene Unclassified Variants Database. The variant was identified in control databases in 113 of 277092 chromosomes at a frequency of 0.0004 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: “Other” in 6 of 6466 chromosomes (freq: 0.001), Latino in 1 of 34390 chromosomes (freq: 0.00003), European Non-Finnish in 27 of 126636 chromosomes (freq: 0.0002), Ashkenazi Jewish in 78 of 10150 chromosomes (freq: 0.008), Finnish in 1 of 25786 chromosomes (freq: 0.00004); it was not observed in the African, East Asian, and South Asian populations. The variant was identified in 2 cases both showing normal IHC from a cohort of patients referred to genetics clinic for suspicion of Lynch Syndrome (Okkels 2012). A study developing a bioinformatics tool that integrates prediction results and structural properties classified this variant as having no impact on MSH6 (Terui 2013). The p.Pro1073 residue is not 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, HumanSpliceFinder) 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.