Submissions for variant NM_000251.3(MSH2):c.1315C>G (p.Pro439Ala)

dbSNP: rs786203116

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000487340	SCV000571801	uncertain significance	not provided	2016-09-26	criteria provided, single submitter	clinical testing	This variant is denoted MSH2 c.1315C>G at the cDNA level, p.Pro439Ala (P439A) at the protein level, and results in the change of a Proline to an Alanine (CCT>GCT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Pro439Ala was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Proline and Alanine differ in some properties, this is considered a semi-conservative amino acid substitution. MSH2 Pro439Ala occurs at a position that is conserved across species and is located in the lever domain, the region of interaction with MSH6, MSH3 and in a region that stabilizes interaction with EXO1 (Lützen 2008). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether MSH2 Pro439Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV001010926	SCV001171191	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-19	criteria provided, single submitter	clinical testing	The p.P439A variant (also known as c.1315C>G), located in coding exon 8 of the MSH2 gene, results from a C to G substitution at nucleotide position 1315. The proline at codon 439 is replaced by alanine, an amino acid with highly similar properties. 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 highly conserved on limited sequence alignment. 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.
Cancer Genomics Group, Japanese Foundation For Cancer Research	RCV001030709	SCV001193631	uncertain significance	Hereditary breast ovarian cancer syndrome	2019-05-01	criteria provided, single submitter	research
Invitae	RCV001851231	SCV002136346	likely benign	Hereditary nonpolyposis colorectal neoplasms	2023-12-12	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001010926	SCV004356677	uncertain significance	Hereditary cancer-predisposing syndrome	2024-01-04	criteria provided, single submitter	clinical testing	This missense variant replaces proline with alanine at codon 439 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). This variant has intermediate MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold -1.32 < LOF score < 0.88, PMID: 33357406). This variant has not been reported in individuals affected with MSH2-related disorders in the literature. This variant has been identified in 2/250892 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.
All of Us Research Program, National Institutes of Health	RCV004003373	SCV004837120	uncertain significance	Lynch syndrome	2024-02-05	criteria provided, single submitter	clinical testing	This missense variant replaces proline with alanine at codon 439 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). This variant has intermediate MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold -1.32 < LOF score < 0.88, PMID: 33357406). This variant has not been reported in individuals affected with MSH2-related disorders in the literature. This variant has been identified in 2/250892 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.