Submissions for variant NM_000251.3(MSH2):c.2459G>A (p.Gly820Asp)

dbSNP: rs794729229

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000466235	SCV000548303	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-11-05	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 820 of the MSH2 protein (p.Gly820Asp). 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: 202204). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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.
Ambry Genetics	RCV000561295	SCV000673867	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-09	criteria provided, single submitter	clinical testing	The p.G820D variant (also known as c.2459G>A) is located in coding exon 15 of the MSH2 gene. The glycine at codon 820 is replaced by aspartic acid, an amino acid with similar properties. This change occurs in the first base pair of coding exon 15. This variant has been identified in an individual with B cell lymphoma (de Miranda NF et al. J Exp Med, 2013 Aug;210:1729-42). 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 01;108:163-175). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000561295	SCV000685047	uncertain significance	Hereditary cancer-predisposing syndrome	2022-06-06	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with aspartic acid at codon 820 of the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MSH2-related hereditary cancer in the literature. 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.
Counsyl	RCV000184050	SCV000784989	uncertain significance	Lynch syndrome 1	2017-03-03	criteria provided, single submitter	clinical testing
Mendelics	RCV000708845	SCV000837855	uncertain significance	Lynch syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000184050	SCV004018267	uncertain significance	Lynch syndrome 1	2023-03-17	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.