Submissions for variant NM_000251.3(MSH2):c.2337G>A (p.Met779Ile)

gnomAD frequency: 0.00001  dbSNP: rs41295292

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160610	SCV000211207	uncertain significance	not provided	2020-07-14	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with colorectal cancer whose tumor demonstrated microsatellite stability and loss of MSH2 and MSH6 (Barnetson 2008); This variant is associated with the following publications: (PMID: 18033691, 21153778)
Ambry Genetics	RCV000572885	SCV000664842	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-05	criteria provided, single submitter	clinical testing	The p.M779I variant (also known as c.2337G>A), located in coding exon 14 of the MSH2 gene, results from a G to A substitution at nucleotide position 2337. The methionine at codon 779 is replaced by isoleucine, an amino acid with highly similar properties. This alteration was detected in one individual with colon cancer whose tumor demonstrated microsatellite stability, but showed absence of the MSH2 and MSH6 proteins on immunohistochemistry (IHC) (Barnetson RA et al. Hum. Mutat., 2008 Mar;29:367-74). This variant was also detected in 0/165 colorectal cancer and/or polyposis patients and was identified in 1/2512 control individuals from a healthy population database (Rosenthal EA et al. Hum Genet, 2018 Oct;137:795-806). In a massively parallel cell-based functional assay testing susceptibility to a DNA damaging agent, 6-thioguanine (6-TG), this variant was reported to be functionally neutral (Jia X et al. Am J Hum Genet, 2021 Jan;108:163-175). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000572885	SCV000690063	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-31	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with isoleucine at codon 779 of the MSH2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). This variant has been reported in an individual affected with colorectal cancer with tumors showing microsatellite stability (PMID: 18033691). This variant has been identified in 1/251450 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.
Invitae	RCV000629729	SCV000750685	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-08-21	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 779 of the MSH2 protein (p.Met779Ile). This variant is present in population databases (rs41295292, gnomAD 0.0009%). This missense change has been observed in individual(s) with colorectal cancer (PMID: 18033691). ClinVar contains an entry for this variant (Variation ID: 90958). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33357406) indicates that this missense variant is not expected to disrupt MSH2 function. 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.
All of Us Research Program, National Institutes of Health	RCV003997161	SCV004825903	uncertain significance	Lynch syndrome	2023-05-04	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with isoleucine at codon 779 of the MSH2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). This variant has been reported in an individual affected with colorectal cancer with tumors showing microsatellite stability (PMID: 18033691). This variant has been identified in 1/251450 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.