ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.751A>G (p.Ile251Val)

gnomAD frequency: 0.00002  dbSNP: rs554884560
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 8
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000215096 SCV000277875 uncertain significance Hereditary cancer-predisposing syndrome 2023-02-27 criteria provided, single submitter clinical testing The p.I251V variant (also known as c.751A>G), located in coding exon 4 of the MSH6 gene, results from an A to G substitution at nucleotide position 751. The isoleucine at codon 251 is replaced by valine, an amino acid with highly similar properties. This alteration was detected in 1/136 families with breast and colon cancer and in 0/332 controls (Wasielewski M et al. Breast Cancer Res Treat. 2010 Sep;123(2):315-20). 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 RCV000220612 SCV000279608 uncertain significance not provided 2023-08-26 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 hereditary breast and colon cancer and in 3 sisters with pancreatic and/or thyroid cancer (Wasielewski et al., 2010; Milella et al., 2022); This variant is associated with the following publications: (PMID: 23621914, 29596542, 22290698, 26333163, 21437237, 19924528, 35901820, 26635394)
Invitae RCV000630227 SCV000751183 likely benign Hereditary nonpolyposis colorectal neoplasms 2024-01-02 criteria provided, single submitter clinical testing
Counsyl RCV000662409 SCV000784839 uncertain significance Lynch syndrome 5 2017-01-04 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000215096 SCV000911421 uncertain significance Hereditary cancer-predisposing syndrome 2023-11-02 criteria provided, single submitter clinical testing This missense variant replaces isoleucine with valine at codon 251 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 a family affected with hereditary breast and colorectal cancer (PMID: 19924528), and in related individuals affected with pancreatic and thyroid cancer (PMID: 35901820). This variant has been identified in 2/251160 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. RCV000662409 SCV004019060 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.
Baylor Genetics RCV003460703 SCV004197576 uncertain significance Endometrial carcinoma 2023-10-26 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV003997102 SCV004836997 uncertain significance Lynch syndrome 2023-11-20 criteria provided, single submitter clinical testing This missense variant replaces isoleucine with valine at codon 251 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 a family affected with hereditary breast and colorectal cancer (PMID: 19924528), and in related individuals affected with pancreatic and thyroid cancer (PMID: 35901820). This variant has been identified in 2/251160 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.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.