Submissions for variant NM_000179.3(MSH6):c.2154C>T (p.Ser718=)

gnomAD frequency: 0.00001  dbSNP: rs771662801

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000162785	SCV000213263	likely benign	Hereditary cancer-predisposing syndrome	2015-11-27	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.
Counsyl	RCV000412468	SCV000489537	likely benign	Lynch syndrome 5	2016-10-18	criteria provided, single submitter	clinical testing
GeneDx	RCV000428690	SCV000513688	likely benign	not specified	2015-12-31	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.
Invitae	RCV001081344	SCV000561447	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-02-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162785	SCV000685259	likely benign	Hereditary cancer-predisposing syndrome	2015-07-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586894	SCV000695801	likely benign	not provided	2017-03-03	criteria provided, single submitter	clinical testing	Variant summary: The MSH6 c.2154C>T (p.Ser718Ser) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. This variant was found in 2/121154 control chromosomes at a frequency of 0.0000165, which does not exceed the estimated maximal expected allele frequency of a pathogenic MSH6 variant (0.0001421). In addition, multiple clinical diagnostic laboratories classified this variant as likely benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases; nor evaluated for functional impact by in vivo/vitro studies. Also, this variant was found together with two DVs in an internal specimen (MUTYH c.1187G>A (p.Gly396Asp) and c.536A>G (p.Tyr179Cys), suggesting that the variant of interest is probably not the cause of the disease. Taken together, this variant is classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV000586894	SCV000805857	likely benign	not provided	2016-12-06	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000162785	SCV002535704	likely benign	Hereditary cancer-predisposing syndrome	2021-06-19	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000412468	SCV004018931	benign	Lynch syndrome 5	2023-03-28	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000428690	SCV004024793	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000586894	SCV004701900	likely benign	not provided	2024-01-01	criteria provided, single submitter	clinical testing	MSH6: BP4, BP7
All of Us Research Program, National Institutes of Health	RCV003995217	SCV004836052	likely benign	Lynch syndrome	2024-01-11	criteria provided, single submitter	clinical testing