Submissions for variant NM_000179.3(MSH6):c.3452C>G (p.Ala1151Gly)

gnomAD frequency: 0.00001  dbSNP: rs587782625

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000132010	SCV000187069	uncertain significance	Hereditary cancer-predisposing syndrome	2021-06-19	criteria provided, single submitter	clinical testing	The p.A1151G variant (also known as c.3452C>G), located in coding exon 6 of the MSH6 gene, results from a C to G substitution at nucleotide position 3452. The alanine at codon 1151 is replaced by glycine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000234247	SCV000283807	likely benign	Hereditary nonpolyposis colorectal neoplasms	2023-11-15	criteria provided, single submitter	clinical testing
Counsyl	RCV000412120	SCV000488229	uncertain significance	Lynch syndrome 5	2016-01-27	criteria provided, single submitter	clinical testing
GeneDx	RCV000484116	SCV000567286	uncertain significance	not provided	2023-10-10	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with uterine cancer (Bhai et al., 2021); This variant is associated with the following publications: (PMID: 17531815, 21120944, 12019211, 34326862)
Mendelics	RCV000708888	SCV000837915	uncertain significance	Lynch syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000132010	SCV000908420	uncertain significance	Hereditary cancer-predisposing syndrome	2022-10-11	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with glycine at codon 1151 of the MSH6 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 3/251416 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Myriad Genetics, Inc.	RCV000412120	SCV004018990	uncertain significance	Lynch syndrome 5	2023-03-29	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000484116	SCV004221224	uncertain significance	not provided	2023-07-08	criteria provided, single submitter	clinical testing	To the best of our knowledge, this variant has not been reported in individuals with MSH6-related conditions in the published literature. In a large case-control study, this variant has been observed in an individual with breast cancer (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/MSH6)). The frequency of this variant in the general population, 0.000026 (3/113722 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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.