Submissions for variant NM_000179.3(MSH6):c.905G>C (p.Arg302Thr)

dbSNP: rs587781510

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129487	SCV000184258	likely benign	Hereditary cancer-predisposing syndrome	2022-12-09	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	RCV000168210	SCV000218875	benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-19	criteria provided, single submitter	clinical testing
GeneDx	RCV000589579	SCV000279833	likely benign	not provided	2019-02-08	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 23621914)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000589579	SCV000601621	uncertain significance	not provided	2023-05-07	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.00038 (13/34584 chromosomes in Latino/Admixed American subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. In a large-scale breast cancer association study, the variant was observed in an individual with breast cancer (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/MSH6)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Color Diagnostics, LLC DBA Color Health	RCV000129487	SCV000685529	likely benign	Hereditary cancer-predisposing syndrome	2023-03-06	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000216085	SCV000695934	likely benign	not specified	2022-12-19	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.905G>C (p.Arg302Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.2e-05 in 251320 control chromosomes, predominantly at a frequency of 0.00038 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH6 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (0.00014), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. To our knowledge, no occurrence of c.905G>C in individuals affected with Hereditary Nonpolyposis Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=9) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign.
Counsyl	RCV000662957	SCV000785927	uncertain significance	Lynch syndrome 5	2018-01-15	criteria provided, single submitter	clinical testing
Mendelics	RCV000708859	SCV000837873	uncertain significance	Lynch syndrome	2018-07-02	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000708859	SCV000890958	uncertain significance	Lynch syndrome	2020-10-22	criteria provided, single submitter	clinical testing	The MSH6 c.905G>C (p.Arg302Thr) missense change has a maximum subpopulation frequency of 0.038% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/2-48026027-G-C). Six 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. To our knowledge, this variant has not been reported in individuals with Lynch syndrome or CMMRD. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: BP4.
Mendelics	RCV000662957	SCV001135798	uncertain significance	Lynch syndrome 5	2019-05-28	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000662957	SCV004019003	likely benign	Lynch syndrome 5	2023-03-29	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
True Health Diagnostics	RCV000129487	SCV000788059	uncertain significance	Hereditary cancer-predisposing syndrome	2017-09-13	no assertion criteria provided	clinical testing