Submissions for variant NM_000251.3(MSH2):c.2375A>G (p.Asn792Ser)

dbSNP: rs587782891

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000132529	SCV000187626	uncertain significance	Hereditary cancer-predisposing syndrome	2021-02-25	criteria provided, single submitter	clinical testing	The p.N792S variant (also known as c.2375A>G), located in coding exon 14 of the MSH2 gene, results from an A to G substitution at nucleotide position 2375. The asparagine at codon 792 is replaced by serine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Counsyl	RCV000409026	SCV000488716	uncertain significance	Lynch syndrome 1	2016-05-27	criteria provided, single submitter	clinical testing
Invitae	RCV000540856	SCV000625373	benign	Hereditary nonpolyposis colorectal neoplasms	2024-02-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000132529	SCV000690065	uncertain significance	Hereditary cancer-predisposing syndrome	2020-11-04	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with serine at codon 792 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 4/251434 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.
GeneDx	RCV001650987	SCV001870995	uncertain significance	not provided	2023-10-31	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; This variant is associated with the following publications: (PMID: 24362816, 36243179, 18822302, 21120944, 31784482)
Genetic Services Laboratory, University of Chicago	RCV001818334	SCV002068673	uncertain significance	not specified	2019-03-13	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000409026	SCV004018311	uncertain significance	Lynch syndrome 1	2023-03-20	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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354926	SCV001549654	uncertain significance	Lynch syndrome		no assertion criteria provided	clinical testing	The MSH2 p.Asn792Ser variant was not identified in the literature nor was it identified in Cosmic, MutDB, UMD-LSDB, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, or Insight Hereditary Tumors Database. The variant was identified in dbSNP (ID: rs587782891, With Uncertain significance allele) and ClinVar (four times as a variant of uncertain significance). The variant was identified in control databases in 4 of 246206 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017) with population frequencies as follows: South Asian in 4 of 30782 chromosomes (freq: 0.0001); and was not observed in the African, Other, Latino, European Non-Finnish, Ashkenazi Jewish, East Asian, or Finnish populations. The p.Asn792 residue is not conserved in mammals and 5 of 5 computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and only 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not reliably predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.