Submissions for variant NM_000251.3(MSH2):c.2455A>G (p.Lys819Glu)

dbSNP: rs1369739730

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000561225	SCV000662273	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-28	criteria provided, single submitter	clinical testing	The p.K819E variant (also known as c.2455A>G), located in coding exon 14 of the MSH2 gene, results from an A to G substitution at nucleotide position 2455. The lysine at codon 819 is replaced by glutamic acid, an amino acid with similar properties. This alteration was identified in 1/1358 non-cancer control individuals and in 0/57 cases in a study looking at cancer predisposition mutations in patients with cutaneous melanoma and a history of at least two additional non-cutaneous melanoma primary cancers (Pritchard AL et al. PLoS One, 2018 Apr;13:e0194098). 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	RCV000561225	SCV001357881	uncertain significance	Hereditary cancer-predisposing syndrome	2020-10-28	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with glutamic acid at codon 819 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/251286 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	RCV001362451	SCV001558467	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2022-09-10	criteria provided, single submitter	clinical testing	Advanced modeling of experimental studies (such as gene expression, population dynamics, functional pathways, and cell-cycle effects in cell culture) performed at Invitae indicates that this missense variant is expected to disrupt MSH2 protein function. ClinVar contains an entry for this variant (Variation ID: 479805). This variant has not been reported in the literature in individuals affected with MSH2-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 819 of the MSH2 protein (p.Lys819Glu). 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.
Sema4, Sema4	RCV000561225	SCV002534477	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-10	criteria provided, single submitter	curation
All of Us Research Program, National Institutes of Health	RCV004000853	SCV004834216	uncertain significance	Lynch syndrome	2023-06-27	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with glutamic acid at codon 819 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/251286 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.