Submissions for variant NM_000251.3(MSH2):c.959C>G (p.Thr320Ser)

dbSNP: rs1064794010

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000484006	SCV000567581	uncertain significance	not provided	2015-08-05	criteria provided, single submitter	clinical testing	This variant is denoted MSH2 c.959C>G at the cDNA level, p.Thr320Ser (T320S) at the protein level, and results in the change of a Threonine to a Serine (ACC>AGC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Thr320Ser was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Threonine and Serine share similar properties, this is considered a conservative amino acid substitution. MSH2 Thr320Ser occurs at a position that is conserved in mammals and is located in the lever domain (Lutzen 2008). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether MSH2 Thr320Ser is pathogenic or benign. We consider it to be a variant of uncertain significance.
Sema4, Sema4	RCV002257761	SCV002526780	uncertain significance	Hereditary cancer-predisposing syndrome	2021-06-29	criteria provided, single submitter	curation
Ambry Genetics	RCV002257761	SCV002694934	uncertain significance	Hereditary cancer-predisposing syndrome	2020-07-22	criteria provided, single submitter	clinical testing	The p.T320S variant (also known as c.959C>G), located in coding exon 6 of the MSH2 gene, results from a C to G substitution at nucleotide position 959. The threonine at codon 320 is replaced by serine, an amino acid with similar properties. 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.
Invitae	RCV002525807	SCV002944825	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-12-22	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 320 of the MSH2 protein (p.Thr320Ser). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MSH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 419642). 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 with a negative predictive value of 80%. 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.
Baylor Genetics	RCV003470544	SCV004196309	uncertain significance	Lynch syndrome 1	2023-08-15	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004002309	SCV004827653	uncertain significance	Lynch syndrome	2023-05-16	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with serine at codon 320 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). In a large breast cancer case-control study, this variant was reported in 1/60465 cases and 1/53460 unaffected controls (PMID: 33471991). This variant has not been identified 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.