Submissions for variant NM_000251.3(MSH2):c.877A>G (p.Thr293Ala)

gnomAD frequency: 0.00001  dbSNP: rs1296650088

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000565509	SCV000669715	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-17	criteria provided, single submitter	clinical testing	The p.T293A variant (also known as c.877A>G), located in coding exon 5 of the MSH2 gene, results from an A to G substitution at nucleotide position 877. The threonine at codon 293 is replaced by alanine, an amino acid with similar properties. This alteration has been reported in an individual with colorectal cancer from China (Xu Y et al. BMC Cancer, 2021 Jan;21:45). 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 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	RCV000565509	SCV000690138	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-09	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with alanine at codon 293 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 suspected of Lynch syndrome (PMID: 33422027). 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.
Invitae	RCV000697645	SCV000826269	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-12-29	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 293 of the MSH2 protein (p.Thr293Ala). 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: 483665). 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.
GeneDx	RCV001653929	SCV001871080	uncertain significance	not provided	2023-08-01	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 an individual with a personal and/or family history suggestive of Lynch syndrome (Xu et al., 2021); This variant is associated with the following publications: (PMID: 27535533, 33422027, 18822302, 21120944)
Baylor Genetics	RCV003459357	SCV004196330	uncertain significance	Lynch syndrome 1	2023-08-04	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV001653929	SCV004224904	uncertain significance	not provided	2022-09-23	criteria provided, single submitter	clinical testing	PM2
All of Us Research Program, National Institutes of Health	RCV004001032	SCV004831577	uncertain significance	Lynch syndrome	2023-11-02	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with alanine at codon 293 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 suspected of Lynch syndrome (PMID: 33422027). 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.