Submissions for variant NM_000179.3(MSH6):c.3758T>A (p.Val1253Glu)

dbSNP: rs202066386

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000656901	SCV000149330	uncertain significance	not provided	2023-07-07	criteria provided, single submitter	clinical testing	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: 28166811, 22949387, 23621914, 25142776, doi:10.5923/j.bioinformatics.20160602.03, 29684080, 25980754, 29945567, 31159747, 26689913, 31422574, 31391288, 31332305, 17531815, 21120944, 31921681, 30267214, 35980532, 36461907, 34445333, 33471991, Giacomazzi2022[preprint])
Ambry Genetics	RCV000115421	SCV000214209	uncertain significance	Hereditary cancer-predisposing syndrome	2022-07-18	criteria provided, single submitter	clinical testing	The p.V1253E variant (also known as c.3758T>A), located in coding exon 8 of the MSH6 gene, results from a T to A substitution at nucleotide position 3758. The valine at codon 1253 is replaced by glutamic acid, an amino acid with dissimilar properties. This alteration has been reported in multiple cohorts of patients undergoing multigene panel testing, including individuals diagnosed with a Lynch syndrome-associated cancer and/or polyps (Tsaousis GN et al. BMC Cancer. 2019 Jun;19:535; Yehia L et al. PLoS Genet. 2018 04;14:e1007352; Yurgelun MB et al. Gastroenterology. 2015 Sep;149:604-13.e20; Young EL et al. BMC Cancer. 2018 Jun;18:697). It was identified in a 70-year-old individual with microsatellite-stable, mismatch repair protein-proficient colorectal cancer (Kraus C et al. Int. J. Cancer. 2015 Mar;136:E559-68), as well as two patients, one with breast and the other with renal cancer, from a cohort of 4034 cancer cases from The Cancer Genome Atlas (Lu C et al. Nat Commun. 2015 Dec;6:10086). Additionally, this alteration was identified in 1/2515 controls and 0/165 individuals with colorectal cancer and/or polyps (Rosenthal EA et al. Hum. Genet. 2018 Oct;137:795-806). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000196523	SCV000254320	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-31	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000212688	SCV000539717	uncertain significance	not specified	2016-10-26	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant has been reported in one individual with CRC. MaxMAF is 0.09%. Classified as DM? in HGMD. Classified in ClinVar as VUS by Invitae, Ambry, GeneDx (2 stars). MAF is greater than or equal to disease prevalence
Color Diagnostics, LLC DBA Color Health	RCV000115421	SCV000685442	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-05	criteria provided, single submitter	clinical testing	This missense variant replaces valine with glutamic acid at codon 1253 of the MSH6 protein. Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with Lynch syndrome-associated cancer and/or polyps (PMID: 25142776, 25980754) and other non-Lynch or unspecified cancers (PMID: 26689913, 29684080, 31921681, 31391288), and in an unaffected individual (PMID: 31422574). This variant has also been identified in 42/282588 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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.
GeneKor MSA	RCV000115421	SCV000822068	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001139791	SCV001299978	uncertain significance	Lynch syndrome 5	2017-10-12	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000212688	SCV001363849	likely benign	not specified	2023-05-01	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.3758T>A (p.Val1253Glu) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, C-terminal domain (IPR000432) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 251190 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 1.62 fold of 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 found primarily in populations of Non-Finnish European origin. c.3758T>A has been reported in the literature in individuals affected with or being tested for Lynch Syndrome, as well as in patients with breast or ovarian cancer (e.g. Kraus_2015, Lu_2015, Young_2018, Yurgelun_2015, Tsaousis_2019, Morak_2019, Li_2020, Kraemer_2019, Oliver_2019, Dorling_2021, Pereira_2022). However, the variant was also identified in many healthy controls (e.g., Dorling_2021, Rosenthal_2018). These reports therefore do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. One publication reports experimental evidence evaluating an impact on RNA splicing and found that the variant had no effect (e.g., Frederiksen_2021). The following publications have been ascertained in the context of this evaluation (PMID: 31422574, 25142776, 31391288, 26689913, 31332305, 31921681, 23621914, 31159747, 29945567, 25980754, 34445333, 35980532, 29684080, 30267214, 33471991). Ten ClinVar submitters (evaluation after 2014) have cited the variant with conflicting assessments: VUS (n = 8) and likely benign (n = 2). Based on the evidence outlined above, the variant was classified as likely benign.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000656901	SCV002010084	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115421	SCV002528061	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-02	criteria provided, single submitter	curation
CeGaT Center for Human Genetics Tuebingen	RCV000656901	SCV002822651	likely benign	not provided	2022-12-01	criteria provided, single submitter	clinical testing	MSH6: PS3:Supporting, BP1, BS1:Supporting
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000212688	SCV004024814	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003467041	SCV004197640	uncertain significance	Endometrial carcinoma	2023-10-11	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997251	SCV004835129	uncertain significance	Lynch syndrome	2024-02-05	criteria provided, single submitter	clinical testing	This missense variant replaces valine with glutamic acid at codon 1253 of the MSH6 protein. Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with Lynch syndrome-associated cancer and/or polyps (PMID: 25142776, 25980754) and other non-Lynch or unspecified cancers (PMID: 26689913, 29684080, 31921681, 31391288), and in an unaffected individual (PMID: 31422574). This variant has also been identified in 42/282588 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355140	SCV001549930	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The MSH6 p.Val1253Glu variant was identified in 1 of 304 proband chromosomes (frequency: 0.003) from individuals or families with colorectal cancer (Kraus 2014). The variant was also identified in dbSNP (ID: rs202066386) as "With Uncertain significance allele”, ClinVar (classified as uncertain significance by Invitae, GeneDx, Ambry Genetics, and three other submitters), and in UMD-LSDB. The variant was identified in control databases in 41 of 276934 chromosomes at a frequency of 0.0002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 5 of 6460 chromosomes (freq: 0.0008), Latino in 1 of 34382 chromosomes (freq: 0.00002), European in 25 of 126474 chromosomes (freq: 0.0002), Finnish in 10 of 25788 chromosomes (freq: 0.0004); it was not observed in the African, Ashkenazi Jewish, East Asian, or South Asian populations. An experimental study on predicting the impact of unclassified genetic variants in MSH6 by the combination of different properties of the protein identified the p.Val1253Glu has an impact on MSH6 (Terui 2013). The p.Val1253 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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.