Submissions for variant NM_000179.3(MSH6):c.3232G>C (p.Val1078Leu)

gnomAD frequency: 0.00004  dbSNP: rs587779932

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000656897	SCV000149316	uncertain significance	not provided	2022-08-18	criteria provided, single submitter	clinical testing	Observed in individuals with a personal or family history including colorectal cancer with normal MSH6 expression, breast/ovarian cancer, prostate cancer, and parathyroid adenoma (Maxwell et al., 2016; Brock et al., 2020; Djursby et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27153395, 33193653, 32052251, 17531815, 21120944)
Invitae	RCV000168205	SCV000218870	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-27	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000656897	SCV000601563	uncertain significance	not provided	2023-03-16	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000023 (3/129138 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in unaffected controls, and in individuals with breast or ovarian cancer (PMIDs: 33471991 (2021), 27153395 (2016)), colorectal cancer (PMID: 33193653 (2020)), and Multiple Endocrine Neoplasia type 4 32052251 (2020). 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.
Ambry Genetics	RCV000567226	SCV000662383	uncertain significance	Hereditary cancer-predisposing syndrome	2022-07-18	criteria provided, single submitter	clinical testing	The p.V1078L variant (also known as c.3232G>C), located in coding exon 5 of the MSH6 gene, results from a G to C substitution at nucleotide position 3232. The valine at codon 1078 is replaced by leucine, an amino acid with highly 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.
Counsyl	RCV000662609	SCV000785254	uncertain significance	Lynch syndrome 5	2017-06-13	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000567226	SCV000911606	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-06	criteria provided, single submitter	clinical testing	This missense variant replaces valine with leucine at codon 1078 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast or ovarian cancer (PMID: 27153395), and in an individual affected with colorectal cancer who also had a pathogenic MUTYH variant (PMID: 33193653). In a large breast cancer case-control study, this variant has been reported in 4/60466 cases and 3/53461 unaffected controls (PMID: 33471991). This variant has been identified in 3/282788 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.	RCV000662609	SCV004019013	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.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000662609	SCV004027752	uncertain significance	Lynch syndrome 5	2023-07-02	criteria provided, single submitter	clinical testing	Criteria applied: PM2_SUP,BP4
All of Us Research Program, National Institutes of Health	RCV003997247	SCV004835013	uncertain significance	Lynch syndrome	2024-02-05	criteria provided, single submitter	clinical testing	This missense variant replaces valine with leucine at codon 1078 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast or ovarian cancer (PMID: 27153395), and in an individual affected with colorectal cancer who also had a pathogenic MUTYH variant (PMID: 33193653). In a large breast cancer case-control study, this variant has been reported in 4/60466 cases and 3/53461 unaffected controls (PMID: 33471991). This variant has been identified in 3/282788 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.