Submissions for variant NM_000251.3(MSH2):c.2551C>G (p.Leu851Val)

dbSNP: rs267608015

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129900	SCV000184718	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-31	criteria provided, single submitter	clinical testing	The p.L851V variant (also known as c.2551C>G), located in coding exon 15 of the MSH2 gene, results from a C to G substitution at nucleotide position 2551. The leucine at codon 851 is replaced by valine, an amino acid with highly similar properties. This alteration was seen in 1/85 Asian patients with personal history of cancer and meeting Amsterdam I/II criteria (Yap HL et al. Fam Cancer, 2009 Aug;8:85-94). 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.
GeneDx	RCV000236960	SCV000293942	uncertain significance	not provided	2021-04-28	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); 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: 22006311, 27930734)
Color Diagnostics, LLC DBA Color Health	RCV000129900	SCV000685054	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-09	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with valine at codon 851 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 reported in an individual affected with colorectal cancer who had two or more family members affected with Lynch syndrome-associated cancers (PMID 18726168), as well as in an individual affected with ovarian, peritoneal, or fallopian tube carcinoma (PMID: 22006311). 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.
Invitae	RCV000698893	SCV000827582	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-13	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 851 of the MSH2 protein (p.Leu851Val). 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: 141396). 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.
All of Us Research Program, National Institutes of Health	RCV003997534	SCV004826431	uncertain significance	Lynch syndrome	2023-08-23	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with valine at codon 851 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 reported in an individual affected with colorectal cancer who had two or more family members affected with Lynch syndrome-associated cancers (PMID 18726168), as well as in an individual affected with ovarian, peritoneal, or fallopian tube carcinoma (PMID: 22006311). 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.