Submissions for variant NM_000179.3(MSH6):c.3233T>C (p.Val1078Ala)

gnomAD frequency: 0.00001  dbSNP: rs376452612

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000200854	SCV000254308	benign	Hereditary nonpolyposis colorectal neoplasms	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000214188	SCV000273366	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-11	criteria provided, single submitter	clinical testing	The p.V1078A variant (also known as c.3233T>C), located in coding exon 5 of the MSH6 gene, results from a T to C substitution at nucleotide position 3233. The valine at codon 1078 is replaced by alanine, an amino acid with similar properties. This variant was identified in a cohort of 681 ancestrally diverse, healthy subjects (Bodian DL et al. PLoS One, 2014 Apr;9:e94554). This alteration was identified in cohorts of patients with pancreatic cancer or other periampullary neoplasms undergoing multigene panel testing (Shindo K et al. J Clin Oncol, 2017 Oct;35:3382-3390; Hu H et al. J Am Coll Surg, 2020 11;231:527-535.e14). 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.
GeneDx	RCV000590417	SCV000568925	uncertain significance	not provided	2023-05-16	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with pancreatic cancer (Shindo et al., 2017; Hu et al., 2020); This variant is associated with the following publications: (PMID: 24728327, 23621914, 17531815, 21120944, 28767289, 32659497)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000590417	SCV000601564	uncertain significance	not provided	2022-12-09	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000035 (4/113696 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with pancreatic ductal adenocarcinoma (PDAC) (PMIDs: 32659497 (2020), 28767289 (2017)) and in individuals with breast cancer in a breast cancer association study (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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000121586	SCV000695846	uncertain significance	not specified	2023-05-15	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.3233T>C (p.Val1078Ala) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, core domain (IPR007696) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 252738 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3233T>C has been reported in the literature as a VUS in settings of multigene panel testing in an individual affected with Pancreatic Ductal Adenocarcinoma (example, Shindo_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer/Lynch syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 23621914, 24728327, 28767289). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS, n=7; Benign, n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Counsyl	RCV000663151	SCV000786303	uncertain significance	Lynch syndrome 5	2018-04-12	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000214188	SCV000903145	uncertain significance	Hereditary cancer-predisposing syndrome	2024-01-03	criteria provided, single submitter	clinical testing	This missense variant replaces valine with alanine 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 pancreatic cancer (PMID: 28767289), and an individual affected with colorectal but with microsatellite stability and detected MSH6 protein by immunohistochemistry (PMID: 29596542). This variant has also been identified in 5/251376 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000590417	SCV001473035	uncertain significance	not provided	2020-03-09	criteria provided, single submitter	clinical testing	The MSH6 c.3233T>C; p.Val1078Ala variant (rs376452612) is reported in the literature in an individual with pancreatic cancer and a family history of prostate cancer (Shindo 2017). This variant is also reported in the ClinVar database (Variation ID: 134855). It is found in the general population with a low overall allele frequency of 0.002% (5/251376 alleles) in the Genome Aggregation Database. The valine at codon 1078 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. However, due to limited information, the clinical significance of this variant is uncertain at this time. REFERENCES Shindo K et al. Deleterious Germline Mutations in Patients With Apparently Sporadic Pancreatic Adenocarcinoma. J Clin Oncol. 2017 Oct 20;35(30):3382-3390.
Sema4, Sema4	RCV000214188	SCV002527989	uncertain significance	Hereditary cancer-predisposing syndrome	2021-04-26	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000663151	SCV004019041	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].
Baylor Genetics	RCV003460855	SCV004197687	uncertain significance	Endometrial carcinoma	2023-09-29	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997353	SCV004835015	uncertain significance	Lynch syndrome	2023-05-30	criteria provided, single submitter	clinical testing	This missense variant replaces valine with alanine 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 pancreatic cancer (PMID: 28767289), and an individual affected with colorectal but with microsatellite stability and detected MSH6 protein by immunohistochemistry (PMID: 29596542). This variant has also been identified in 5/251376 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.
ITMI	RCV000121586	SCV000085782	not provided	not specified	2013-09-19	no assertion provided	reference population