Submissions for variant NM_000179.3(MSH6):c.2400T>C (p.Val800=)

gnomAD frequency: 0.00001  dbSNP: rs267608071

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000524142	SCV000283749	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-11	criteria provided, single submitter	clinical testing
GeneDx	RCV001171950	SCV000513691	likely benign	not provided	2018-08-30	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 19250818, 23523604)
Ambry Genetics	RCV000491664	SCV000580206	likely benign	Hereditary cancer-predisposing syndrome	2016-04-13	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.
Color Diagnostics, LLC DBA Color Health	RCV000491664	SCV000690258	likely benign	Hereditary cancer-predisposing syndrome	2016-04-29	criteria provided, single submitter	clinical testing
Counsyl	RCV000663185	SCV000786356	likely benign	Lynch syndrome 5	2018-04-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000427895	SCV000917782	likely benign	not specified	2018-10-23	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.2400T>C alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4.1e-06 in 245490 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.2400T>C, has been reported in the literature in one individual affected with Lynch Syndrome which had a co-occurrence with another pathogenic MSH2 variant, c.229_230delAG (p.Ser77fsX4), providing supporting evidence for a benign role (Perez-Cabornero_2013). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
CeGaT Center for Human Genetics Tuebingen	RCV001171950	SCV001334862	likely benign	not provided	2024-03-01	criteria provided, single submitter	clinical testing	MSH6: BP4, BP7
Mendelics	RCV000427895	SCV002519705	benign	not specified	2022-05-04	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000491664	SCV002535733	likely benign	Hereditary cancer-predisposing syndrome	2021-11-01	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000663185	SCV004019007	benign	Lynch syndrome 5	2023-03-29	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.
PreventionGenetics, part of Exact Sciences	RCV004537275	SCV004753589	likely benign	MSH6-related disorder	2019-10-18	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
All of Us Research Program, National Institutes of Health	RCV003997076	SCV004834321	likely benign	Lynch syndrome	2023-12-01	criteria provided, single submitter	clinical testing