Submissions for variant NM_000251.3(MSH2):c.14C>G (p.Pro5Arg)

dbSNP: rs56170584

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000546654	SCV000625273	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-16	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 5 of the MSH2 protein (p.Pro5Arg). 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: 455500). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33357406) indicates that this missense variant is not expected to disrupt MSH2 function with a negative predictive value of 80%. 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.
Color Diagnostics, LLC DBA Color Health	RCV000579789	SCV000684941	uncertain significance	Hereditary cancer-predisposing syndrome	2024-01-16	criteria provided, single submitter	clinical testing	This missense variant replaces proline with arginine at codon 5 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 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 a family affected with Lynch syndrome-associated cancers (PMID: 14692024). 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.
Ambry Genetics	RCV000579789	SCV001172270	likely benign	Hereditary cancer-predisposing syndrome	2023-01-26	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.
GeneDx	RCV002274057	SCV002559446	uncertain significance	not provided	2023-09-22	criteria provided, single submitter	clinical testing	Observed in an individual with a family history of MSH2-related cancers (Lynch et al., 2004); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32019277, 18822302, 21120944, 14692024)
CeGaT Center for Human Genetics Tuebingen	RCV002274057	SCV003916100	uncertain significance	not provided	2023-03-01	criteria provided, single submitter	clinical testing	MSH2: PP3
All of Us Research Program, National Institutes of Health	RCV004003736	SCV004826227	uncertain significance	Lynch syndrome	2023-08-15	criteria provided, single submitter	clinical testing	This missense variant replaces proline with arginine at codon 5 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). A functional study reported that this variant may not impact DNA mismatch repair activity based on a 6-thioguanine sensitivity assay in Msh2-deficient haploid human cells (PMID: 33357406). This variant has been observed in a suspected Lynch syndrome family (PMID: 14692024). 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.