Submissions for variant NM_000179.3(MSH6):c.431G>T (p.Ser144Ile)

gnomAD frequency: 0.00158  dbSNP: rs3211299

Total submissions: 29

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000074988	SCV000108204	no known pathogenicity	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Multifactorial likelihood analysis posterior probability <0.001
GeneDx	RCV000121570	SCV000170368	benign	not specified	2014-01-09	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics	RCV000130532	SCV000185401	benign	Hereditary cancer-predisposing syndrome	2014-11-10	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001081952	SCV000252631	benign	Hereditary nonpolyposis colorectal neoplasms	2024-02-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000121570	SCV000302879	likely benign	not specified		criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000121570	SCV000539698	benign	not specified	2020-08-10	criteria provided, single submitter	clinical testing	The p.Ser144Ile variant in MSH6 has been reported in 19 papers in HGMD as benign or inconclusive and Invitae classified variant as benign in 2019. It has also been identified in 0.21% (52/25120) of Finnish chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 41596). In summary, while the clinical significance of this variant is uncertain, its frequency suggests that it is more likely to be benign. ACMG/AMP Criteria applied: BA1.
Genetic Services Laboratory, University of Chicago	RCV000121570	SCV000595849	likely benign	not specified	2016-12-15	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130532	SCV000685489	likely benign	Hereditary cancer-predisposing syndrome	2015-02-19	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000034501	SCV000695914	benign	not provided	2016-05-03	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000121570	SCV000700619	benign	not specified	2016-11-21	criteria provided, single submitter	clinical testing
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000606030	SCV000781780	uncertain significance	Lynch syndrome 5	2016-11-01	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000121570	SCV000888289	benign	not specified	2020-07-10	criteria provided, single submitter	clinical testing
Mendelics	RCV000606030	SCV001135784	likely benign	Lynch syndrome 5	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000606030	SCV001300595	benign	Lynch syndrome 5	2018-02-13	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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001198193	SCV001369063	uncertain significance	Endometrial carcinoma	2019-05-08	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP3,PP4,BS1,BS2.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798061	SCV002042060	likely benign	Breast and/or ovarian cancer	2023-06-21	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000130532	SCV002536320	benign	Hereditary cancer-predisposing syndrome	2020-02-06	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000121570	SCV002552275	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000034501	SCV002563569	benign	not provided	2024-08-01	criteria provided, single submitter	clinical testing	MSH6: BP4, BS3:Supporting, BS1, BS2
Genetics and Molecular Pathology, SA Pathology	RCV000606030	SCV002761387	benign	Lynch syndrome 5	2019-10-10	criteria provided, single submitter	clinical testing
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034501	SCV000043350	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.
ITMI	RCV000121570	SCV000085766	not provided	not specified	2013-09-19	no assertion provided	reference population
CSER _CC_NCGL, University of Washington	RCV000148642	SCV000190357	likely benign	Colorectal cancer, non-polyposis	2014-06-01	no assertion criteria provided	research
Mayo Clinic Laboratories, Mayo Clinic	RCV000034501	SCV000257299	likely benign	not provided	2022-09-15	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353551	SCV000592567	likely benign	Carcinoma of colon		no assertion criteria provided	clinical testing	MSH6, EXON2, c.431G>T, p.Ser144Ile, Heterozygous, Likely Benign The MSH6 p.Ser144Ile variant was identified in 5 of 4526 proband chromosomes (frequency: 0.001) from individuals or families with HNPCC, suspected HNPCC, or CRC before age 50, and was present in 3 of 1554 control chromosomes (frequency: 0.002) from healthy individuals (Niessen 2006, Nilbert 2009, Okkels 2012, Woods 2005, Bodian 2014). The variant was also identified in dbSNP (ID: rs3211299) as "With other allele", ClinVar (classified as benign by Invitae, GeneDx, Ambry Genetics, and 4 other submitters; as likely benign by Prevention Genetics, our laboratory, and 6 other submitters; and as uncertain significance by 2 submitters), LOVD 3.0 (34x), and UMD-LSDB (15x as neutral). In UMD, the variant was identified with multiple co-occurring pathogenic variants: MSH6, c.2906A>G (p.Tyr969Cys); MLH1, c.380G>C (p.Arg127Thr); and MSH2 c.1277_1386del, (p.Lys427GlyfsX4), increasing the likelihood that the p.Ser144Ile variant does not have clinical significance. The variant was identified in control databases in 275 of 277216 chromosomes at a frequency of 0.001, 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 10 of 24036 chromosomes (freq: 0.0004), Other in 9 of 6466 chromosomes (freq: 0.001), Latino in 29 of 34418 chromosomes (freq: 0.0008), European in 173 of 126702 chromosomes (freq: 0.001), and Finnish in 54 of 25790 chromosomes (freq: 0.002); it was not observed in the Ashkenazi Jewish, East Asian, or South Asian populations. Although the p.Ser144 residue is not conserved in mammals and other organisms, computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Ile variant may impact the protein. 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; this is not very predictive of pathogenicity. Functional and bioinformatics assays show somewhat conflicting results in terms of pathogenicity of this variant: one study showed loss of function for this variant in a yeast assay (Kolodner 1999), while multiple other studies found the interaction of the variant protein with MSH2 and the MMR activity to be comparable to wildtype (Perez-Cabornero 2013, Bameston 2008, Drost 2012, Cyr 2008, Kariola 2002). 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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000606030	SCV000734208	likely benign	Lynch syndrome 5		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000606030	SCV000745646	benign	Lynch syndrome 5	2016-12-09	no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000034501	SCV001924899	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000121570	SCV001956081	benign	not specified		no assertion criteria provided	clinical testing