Submissions for variant NM_000179.3(MSH6):c.3283C>T (p.Arg1095Cys)

gnomAD frequency: 0.00006  dbSNP: rs376243329

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000586502	SCV000149322	uncertain significance	not provided	2023-09-07	criteria provided, single submitter	clinical testing	Published functional studies demonstrate no damaging effect: proficient mismatch repair activity (Houlleberghs et al., 2017); 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: 23621914, 24728327, 31013963, 26845104, 12522549, 30159786, 30093976, 31386297, 24448499, 31391288, 29044863, 17531815, 21120944, 28531214, 33471991, 25085752, 36243179)
Ambry Genetics	RCV000115413	SCV000172721	likely benign	Hereditary cancer-predisposing syndrome	2020-02-18	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	RCV001080360	SCV000260901	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-19	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000204658	SCV000266209	uncertain significance	Lynch syndrome	2015-11-20	criteria provided, single submitter	clinical testing
Counsyl	RCV000412360	SCV000488103	uncertain significance	Lynch syndrome 5	2015-12-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115413	SCV000685382	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-07	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 1095 of the MSH6 protein. Computational prediction 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 reported for this variant. This variant has been observed in individuals affected with Lynch syndrome-associated cancers (PMID: 12522549, 26845104, 30093976, 31391288), breast cancer (PMID: 30159786) and an unspecified cancer (PMID: 31391288). This variant also has been observed in a pancreatic cancer case-control study in multiple unaffected individuals and absent in affected individuals (PMID: 32980694), and in a breast cancer case-control study in both affected and unaffected individuals (PMID: 33471991). This variant has been identified in 23/282860 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000121585	SCV000695855	likely benign	not specified	2021-06-21	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.3283C>T (p.Arg1095Cys) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, core domain 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 8.4e-05 in 251452 control chromosomes, predominantly at a frequency of 0.00014 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is approximately the same as expected for a pathogenic variant in MSH6 causing Hereditary Nonpolyposis Colorectal Cancer (0.00014 vs 0.00014), supporting a benign outcome. c.3283C>T has been reported in the literature in settings of multigene cancer panel testing among individuals affected with Lynch Syndrome (example Shirts_2015, Kanchi_2014, Li_2020). One of these reports estimated the tumor characteristic likelihood ratio (TCLR) for this variant as likely benign (Li_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant in an MMR (mismatch repair) assay (Houlleberghs_2017). Eight 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, n=2; VUS, n=6). Some submitters cite overlapping evidence utilized in the context of this evaluation and at-least one submitter has re-classified this variant as likely benign since its previous evaluation. Based on the evidence outlined above, the variant was re-classified as likely benign.
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000412360	SCV000781792	uncertain significance	Lynch syndrome 5	2016-11-01	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000586502	SCV001152302	uncertain significance	not provided	2022-05-01	criteria provided, single submitter	clinical testing	MSH6: PP2, BS3:Supporting
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798330	SCV002042049	uncertain significance	Breast and/or ovarian cancer	2022-09-13	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115413	SCV002528003	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-10	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000412360	SCV004018957	benign	Lynch syndrome 5	2023-03-29	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. This variant has been observed in conjunction with multiple pathogenic variants, reducing the likelihood this variant itself is pathogenic.
Baylor Genetics	RCV003460816	SCV004197629	uncertain significance	Endometrial carcinoma	2023-10-13	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000204658	SCV004835035	uncertain significance	Lynch syndrome	2024-01-11	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 1095 of the MSH6 protein. Computational prediction 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 reported for this variant. This variant has been observed in individuals affected with Lynch syndrome-associated cancers (PMID: 12522549, 26845104, 30093976, 31391288), breast cancer (PMID: 30159786) and an unspecified cancer (PMID: 31391288). This variant also has been observed in a pancreatic cancer case-control study in multiple unaffected individuals and absent in affected individuals (PMID: 32980694), and in a breast cancer case-control study in both affected and unaffected individuals (PMID: 33471991). This variant has been identified in 23/282860 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.
ITMI	RCV000121585	SCV000085781	not provided	not specified	2013-09-19	no assertion provided	reference population
Clinical Genetics, Academic Medical Center	RCV000586502	SCV001926147	uncertain significance	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000586502	SCV001963275	uncertain significance	not provided		no assertion criteria provided	clinical testing