ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1099G>A (p.Val367Ile) (rs80285180)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000546747 SCV000625226 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2020-09-17 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 367 of the MSH2 protein (p.Val367Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is not present in population databases (rs80285180, ExAC no frequency). This variant has been observed in an individual affected with pancreatic cancer (PMID: 19728162). ClinVar contains an entry for this variant (Variation ID: 455471). Experimental studies have shown that this missense change does not affect the mismatch repair activity of the MSH2 protein (PMID: 19728162,22581703). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Health, Inc RCV000776438 SCV000911924 likely benign Hereditary cancer-predisposing syndrome 2017-01-23 criteria provided, single submitter clinical testing
Ambry Genetics RCV000776438 SCV001178348 uncertain significance Hereditary cancer-predisposing syndrome 2019-12-05 criteria provided, single submitter clinical testing The p.V367I variant (also known as c.1099G>A), located in coding exon 7 of the MSH2 gene, results from a G to A substitution at nucleotide position 1099. The valine at codon 367 is replaced by isoleucine, an amino acid with highly similar properties. This alteration has been detected in conjunction with MSH2 p.E205Q (phase unknown) in an Italian patient diagnosed with pancreatic cancer at age 59y whose family history includes a father with bladder cancer at age 70y, a maternal aunt with endometrial cancer at 45y, and a maternal cousin with colon cancer at 61y; MSI and/or MMR IHC studies were not performed on any of the cancers and segregation analysis of the two MSH2 alterations could not performed (Gargiulo S et al. Fam Cancer. 2009;8(4):547-53). In vitro MMR assays did not show a significant decrease in repair capability (Gargiulo S et al. Fam Cancer. 2009;8(4):547-53; Kantelinen J et al. Hum Mutat. 2012 Aug;33(8):1294-301). This amino acid position is highly 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 RCV001561760 SCV001784416 likely benign not provided 2020-12-02 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29641532, 28912153, 19728162, 22581703)

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