Submissions for variant NM_000251.3(MSH2):c.743A>G (p.Lys248Arg)

dbSNP: rs1064794704

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000757471	SCV000569767	uncertain significance	not provided	2016-03-30	criteria provided, single submitter	clinical testing	This variant is denoted MSH2 c.743A>G at the cDNA level, p.Lys248Arg (K248R) at the protein level, and results in the change of a Lysine to an Arginine (AAA>AGA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Lys248Arg 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 Lysine and Arginine share similar properties, this is considered a conservative amino acid substitution. MSH2 Lys248Arg occurs at a position where amino acids with properties similar to Lysine are tolerated across species and is located in the connector domain (Lützen 2008). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether MSH2 Lys248Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000757471	SCV000885712	uncertain significance	not provided	2017-08-24	criteria provided, single submitter	clinical testing	The MSH2 c.743A>G; p.Lys248Arg variant (rs1064794704) has not been reported in the literature. It is listed in the ClinVar database (Variation ID: 420794), and is found in the general population with an overall allele frequency of 0.0004 percent (1/246214 alleles) in the Genome Aggregation Database. The lysine at codon 248 is moderately conserved, and computational programs (SIFT, PolyPhen2, Align GVGD) predict this variant to be tolerated. However, with the lack of information regarding p.Lys248Arg, its clinical significance is uncertain at this time. References: Link to ClinVar database for p.Lys248Arg: https://www.ncbi.nlm.nih.gov/clinvar/variation/420794/
Color Diagnostics, LLC DBA Color Health	RCV000775779	SCV000910226	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-05	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with arginine at codon 248 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 identified in an individual affected with breast cancer (PMID: 33471991). This variant has been identified in 1/251394 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000757471	SCV001134373	uncertain significance	not provided	2018-10-09	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000775779	SCV001188818	likely benign	Hereditary cancer-predisposing syndrome	2022-08-08	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Invitae	RCV001046068	SCV001209953	benign	Hereditary nonpolyposis colorectal neoplasms	2023-10-30	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000775779	SCV002526739	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-23	criteria provided, single submitter	curation
All of Us Research Program, National Institutes of Health	RCV001824799	SCV004829049	uncertain significance	Lynch syndrome	2023-08-15	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with arginine at codon 248 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 identified in an individual affected with breast cancer (PMID: 33471991). This variant has been identified in 1/251394 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.
GenomeConnect, ClinGen	RCV001824799	SCV002075201	not provided	Lynch syndrome		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 08-31-2020 by Lab or GTR ID 239772. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.