Submissions for variant NM_000179.2(MSH6):c.984C>T (p.Ser328=) (rs138143769)

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212638	SCV000170349	benign	not specified	2014-02-14	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	RCV000126823	SCV000213111	likely benign	Hereditary cancer-predisposing syndrome	2014-06-24	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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	RCV001081374	SCV000252632	benign	Hereditary nonpolyposis colorectal neoplasms	2020-11-25	criteria provided, single submitter	clinical testing
Counsyl	RCV000409252	SCV000488839	likely benign	Hereditary nonpolyposis colorectal cancer type 5	2016-06-29	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000212638	SCV000595846	likely benign	not specified	2017-04-17	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212638	SCV000601624	benign	not specified	2017-05-01	criteria provided, single submitter	clinical testing
Color Health, Inc	RCV000126823	SCV000685532	benign	Hereditary cancer-predisposing syndrome	2015-09-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588033	SCV000695936	benign	not provided	2016-01-04	criteria provided, single submitter	clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics	RCV000212638	SCV000706960	likely benign	not specified	2017-04-28	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000588033	SCV000889513	benign	not provided	2017-05-01	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories	RCV000212638	SCV001158617	benign	not specified	2019-06-21	criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,Illumina	RCV000409252	SCV001302621	likely benign	Hereditary nonpolyposis colorectal cancer type 5	2017-04-28	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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Department of Pathology and Laboratory Medicine,Sinai Health System	RCV001355092	SCV001549867	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The MSH6 p.Ser328Ser= variant was not identified in the literature. The variant was identified in dbSNP (rs138143769) as “with uncertain significance, other allele”, ClinVar (classified as benign by Invitae, GeneDx, Color and 3 other submitters; and as likely benign by Ambry Genetics, Eurofins, Counsyl and 1 other submitter) and UMD-LSDB (observed 1x). The variant was identified in control databases in 81 of 282,780 chromosomes (1 homozygous) at a frequency of 0.0003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 72 of 24,954 chromosomes (freq: 0.003, increasing the likelihood this could be a low frequency benign variant), Latino in 5 of 35,436 chromosomes (freq: 0.0001), and European in 4 of 129,118 chromosomes (freq: 0.00003), while it was not observed in the Ashkenazi Jewish, East Asian, Finnish, Other, or South Asian populations. The p.Ser328= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. The variant occurs at a non-highly conserved nucleotide 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. 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.