Submissions for variant NM_000179.3(MSH6):c.241G>A (p.Ala81Thr)

gnomAD frequency: 0.00001  dbSNP: rs587779239

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000074747	SCV000107956	likely benign	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Multifactorial likelihood analysis posterior probability 0.001-0.049
Ambry Genetics	RCV000213900	SCV000273913	likely benign	Hereditary cancer-predisposing syndrome	2018-12-24	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	RCV000627691	SCV000551067	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-24	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000487781	SCV000575206	uncertain significance	not provided	2016-10-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000213900	SCV000911850	benign	Hereditary cancer-predisposing syndrome	2016-09-06	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780462	SCV000917729	uncertain significance	not specified	2017-11-03	criteria provided, single submitter	clinical testing	Variant summary: The MSH6 c.241G>A (p.Ala81Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 1/30778 control chromosomes in gnomAD at a frequency of 0.0000325, which does not exceed the estimated maximal expected allele frequency of a pathogenic MSH6 variant (0.0001421). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign/VUS. The variant of interest has not, to our knowledge, been reported in affected individuals via publications; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS).
GeneDx	RCV000487781	SCV001822662	uncertain significance	not provided	2019-08-27	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); While protein-based in silico analysis supports that this variant does not alter protein structure/function, splice predictors suggest this variant may impact gene splicing. In the absence of RNA or functional studies, the actual effect of this sequence change is unknown.; Has not been previously published as pathogenic or benign to our knowledge; Variant reported as benign or likely benign by a well-established clinical consortium and/or database (Thompson 2014); This variant is associated with the following publications: (PMID: 23104009, 26552419, 23621914, 22290698, 30212499)
All of Us Research Program, National Institutes of Health	RCV000074747	SCV004828637	benign	Lynch syndrome	2023-12-13	criteria provided, single submitter	clinical testing