Submissions for variant NM_000179.3(MSH6):c.3203G>A (p.Arg1068Gln)

gnomAD frequency: 0.00012  dbSNP: rs398123230

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000679234	SCV000110153	uncertain significance	not provided	2013-06-07	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000131252	SCV000186214	likely benign	Hereditary cancer-predisposing syndrome	2018-08-28	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.
Invitae	RCV001083147	SCV000218795	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-28	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000168135	SCV000266208	uncertain significance	Lynch syndrome	2015-11-20	criteria provided, single submitter	clinical testing
GeneDx	RCV000679234	SCV000279106	likely benign	not provided	2020-11-06	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 26689913, 25503501, 23047549, 23104009, 27978560, 26845104, 22495361, 29625052)
Illumina Laboratory Services, Illumina	RCV000168135	SCV000430974	uncertain significance	Lynch syndrome	2016-06-14	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000217757	SCV000601561	uncertain significance	not specified	2017-03-29	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000679234	SCV000805880	uncertain significance	not provided	2017-12-05	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131252	SCV000902892	likely benign	Hereditary cancer-predisposing syndrome	2022-01-02	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000168135	SCV001450730	uncertain significance	Lynch syndrome	2020-10-15	criteria provided, single submitter	clinical testing	The MSH6 c.3203G>A (p.Arg1068Gln) missense change has a maximum subpopulation frequency of 0.028% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/2-48030589-G-A). Five of seven in silico tools predict a benign effect of this variant on protein function (BP4), but these predictions have not been confirmed by functional studies. This variant has been reported in individuals with colorectal cancer and microsatellite stability or normal mismatch repair immunohistochemistry in the tumor (PMID: 26845104, 27978560). It has also been reported in individuals with sporadic pancreatic ductal adenocarcinoma (PMID: 32659497, 28767289), breast cancer (PMID: 25503501), epithelial ovarian cancer (PMID: 23047549), and pediatric medulloblastoma (PMID: 26580448). Data submitted to ClinVar indicates that this variant did not segregate with disease in a family study (ClinVar Accession: SCV000186214.6). In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: BP4.
Sema4, Sema4	RCV000131252	SCV002535802	likely benign	Hereditary cancer-predisposing syndrome	2022-02-14	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000217757	SCV002552325	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000679234	SCV004224912	uncertain significance	not provided	2022-11-04	criteria provided, single submitter	clinical testing	BP4
CeGaT Center for Human Genetics Tuebingen	RCV000679234	SCV004699632	likely benign	not provided	2023-12-01	criteria provided, single submitter	clinical testing	MSH6: BP4
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356423	SCV001551587	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The MSH6 p.Arg1068Gln variant was identified in 3 of 3116 proband chromosomes (frequency: 0.00096) from individuals or families with colorectal cancer, HNPCC, or breast cancer (Hampel 2018, Maxwell 2015, Okkels 2012). The variant was also identified in dbSNP (ID: rs398123230) as "With Uncertain significance, other allele", in ClinVar and Clinvitae (classified as likely benign by Ambry Genetics, Invitae and GeneDx; classified as uncertain significance by EGL, University of Washington, Illumina, Quest Diagnostics and Prevention Genetics), and UMD-LSDB (found to be co-occurring with a pathogenic MSH6 variant: c.2764C>T, p.Arg922X in 2 cases). The variant was not identified in COSMIC, MutDB, Insight Colon Cancer Gene Variant Database, Mismatch Repair Genes Variant Database, or Insight Hereditary Tumors databases. The variant was identified in control databases in 31 of 277070 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 7 of 24028 chromosomes (freq: 0.0003), Latino in 1 of 34386 chromosomes (freq: 0.00003), European Non-Finnish in 23 of 126620 chromosomes (freq: 0.0002); it was not observed in the Other, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Arg1068 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein. 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; however, this information is not predictive enough to rule out pathogenicity. 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.