Submissions for variant NM_000179.3(MSH6):c.3299C>T (p.Thr1100Met)

dbSNP: rs63750442

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CSER _CC_NCGL, University of Washington	RCV000074836	SCV000212177	uncertain significance	Lynch syndrome	2015-03-11	criteria provided, single submitter	research
Invitae	RCV000524169	SCV000254313	benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000622259	SCV000274229	uncertain significance	Inborn genetic diseases	2016-07-28	criteria provided, single submitter	clinical testing
GeneDx	RCV000587747	SCV000279107	uncertain significance	not provided	2023-09-21	criteria provided, single submitter	clinical testing	Observed in patients with melanoma, thyroid, colorectal, or other Lynch syndrome-associated cancers, co-segregating with CRC in one family together with a MUTYH pathogenic variant (Berends et al., 2002; Yurgelun et al., 2015; de Voer et al., 2016; Rosenthal et al., 2018; Yehia et al., 2018; Schubert et al., 2020); Published functional studies demonstrate no damaging effect: mismatch repair activity similar to wild-type (Schubert et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25801821, 32615015, 32980694, 25980754, 23621914, 24362816, 26269718, 26901136, 11709755, 35422474, 32658311, 33471991, 29684080, 17531815, 21120944, 30267214, 31422818, 32068069)
Color Diagnostics, LLC DBA Color Health	RCV000218926	SCV000685385	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-05	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with methionine at codon 1100 of the MSH6 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study has reported that this variant does not impact in vitro DNA mismatch repair activity (PMID: 32615015). This variant has been reported in individuals affected with Lynch syndrome-associated cancer and/or polyps (PMID: 11709755, 25980754, 26901136, 30267214) and skin melanoma and thyroid cancer (PMID: 2968408). This variant also has been reported to cosegregate with heterozygous pathogenic MUTYH p.Tyr179Cys in three colorectal cancer-affected members of a suspected Lynch syndrome family (PMID: 32615015). This variant has been identified in 12/282832 chromosomes in the general population by the Genome Aggregation Database (gnomAD) and in healthy controls (PMID: 32980694). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000223174	SCV000695856	uncertain significance	not specified	2022-12-27	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.3299C>T (p.Thr1100Met) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 251432 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MSH6 causing Hereditary Nonpolyposis Colorectal Cancer (4e-05 vs 0.00014), allowing no conclusion about variant significance. c.3299C>T has been reported in the literature in individuals affected with or suspected to have Hereditary Nonpolyposis Colorectal Cancer, or colorectal cancer or breast cancer (Example: Ackay_2021, Schuber_2020, Berends_2002, deVoer_2016, Kwong_2020). The variant was also reported to cosegregate with heterozygous pathogenic MUTYH p.Tyr179Cys in multiple colorectal cancer-affected members of a suspected Lynch syndrome family (Schuber_2020). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. At least one publication reports experimental evidence evaluating an impact on protein function (Schuber_2020). These results showed no damaging effect of this variant. 12 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000223174	SCV000731376	uncertain significance	not specified	2017-01-25	criteria provided, single submitter	clinical testing	The p.Thr1100Met variant in MSH6 has been reported in 2 individuals with suspect ed colorectal cancer or Lynch syndrome (Berends 2002, Yurgelun 2015). This varia nt has also been identified in 2/16512 of South Asian chromosomes by the Exome A ggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs63750442). Computational prediction tools and conservation analysis do not provide strong s upport for or against an impact to the protein. In addition, the p.Thr1100Met va riant has been classified as a variant of uncertain significance on Sept 5, 2013 by the ClinGen-approved InSiGHT expert panel (ClinVar SCV000108047.2). In summ ary, the clinical significance of the p.Thr1100Met variant is uncertain.
Fulgent Genetics, Fulgent Genetics	RCV000764431	SCV000895488	uncertain significance	Endometrial carcinoma; Mismatch repair cancer syndrome 1; Lynch syndrome 5	2018-10-31	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587747	SCV001134427	uncertain significance	not provided	2023-05-03	criteria provided, single submitter	clinical testing	In the published literature, the variant has been reported in individuals with colorectal cancer (PMIDs: 11709755 (2002), 26901136 (2016), 32658311 (2021), 30267214 (2018)), breast cancer (PMID: 32068069 (2020)) and suspected lynch syndrome (25980754 (2015)). In one family, this variant was found to co-occur with a pathogenic MUTYH variant in 3 individuals with colorectal cancer (PMID: 32615015 (2020)). One functional study demonstrated this variant has a mismatch repair efficiency similar to wildtype MSH6 in vitro (PMID: 32615015 (2020)). The frequency of this variant in the general population, 0.000031 (4/129154 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Ambry Genetics	RCV000218926	SCV001181176	uncertain significance	Hereditary cancer-predisposing syndrome	2022-10-17	criteria provided, single submitter	clinical testing	The p.T1100M variant (also known as c.3299C>T), located in coding exon 5 of the MSH6 gene, results from a C to T substitution at nucleotide position 3299. The threonine at codon 1100 is replaced by methionine, an amino acid with similar properties. This alteration has been reported in multiple individuals diagnosed with colorectal cancer (Berends M. et al. Am. J. Hum. Genet. 2002 Jan;70(1):26-37; de Voer RM et al. PLoS Genet., 2016 Feb;12:e1005880). This alteration was also detected in a study of 1,165 individuals with a history of colorectal cancer or colon polyps as well as 590 controls (Gordon AS et al. Am J Hum Genet, 2019 09;105:526-533). Additionally, this alteration was seen in 0/732 breast cancer patients, 1/189 colorectal cancer patients and 0/490 cancer-free elderly controls in a Turkish population (Akcay IM et al. Int J Cancer, 2021 01;148:285-295). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Genetic Services Laboratory, University of Chicago	RCV000223174	SCV002070933	uncertain significance	not specified	2019-09-23	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000218926	SCV002528006	uncertain significance	Hereditary cancer-predisposing syndrome	2021-06-04	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000223174	SCV002552336	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003460680	SCV004197569	uncertain significance	Endometrial carcinoma	2023-10-26	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003944986	SCV004764327	uncertain significance	MSH6-related condition	2024-02-26	criteria provided, single submitter	clinical testing	The MSH6 c.3299C>T variant is predicted to result in the amino acid substitution p.Thr1100Met. This variant has been reported in individuals with Lynch syndrome-associated cancers such as colorectal cancers and in controls (Examples: Table 1. Berends et al 2002. PubMed ID: 11709755; Supplemental Table 2. Yurgelun et al 2015. PubMed ID: 25980754; Supplemental Table 2. Rosenthal EA et al 2018. PubMed ID: 30267214; Table S2. Okawa et al 2022. PubMed ID: 36243179). This variant is reported in 0.0080% of alleles in individuals of African descent in gnomAD and is interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/89369/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358521	SCV001554277	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The MSH6 p.Thr1100Met variant was identified in 3 of 3262 proband chromosomes (frequency: 0.001) from individuals or families with colorectal cancer (Berends 2002, de Voer 2016, Yurgelun 2015). The variant was also identified in dbSNP (ID: rs63750442) as With Uncertain significance allele, ClinVar (classified as uncertain significance by Invitae, Ambry Genetics, GeneDx, Color Genomics, and 5 clinical laboratories), Clinvitae, Cosmic, MutDB, UMD-LSDB (1X classified as uncertain significance), Mismatch Repair Genes Variant Database, and Insight Hereditary Tumors Database (as unclassified variant) databases. The variant was not identified in GeneInsight-COGR, or the Zhejiang Colon Cancer Database. The variant was identified in control databases in 11 of 277180 chromosomes at a frequency of 0.00004 (Genome Aggregation Database Feb 27, 2017). The variant was identified in the following populations: African in 2 of 24038 chromosomes (freq: 0.0001), “Other” in 1 of 6464 chromosomes (freq: 0.0002), European in 5 of 126684 chromosomes (freq: 0.00004), East Asian in 1 of 18868 chromosomes (freq: 0.0001), and South Asian in 2 of 30782 chromosomes (freq: 0.0001), while the variant was not observed in the Latino, Ashkenazi Jewish, or Finnish populations. The p.Thr1100 residue is 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 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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.