Submissions for variant NM_000251.3(MSH2):c.2354A>C (p.His785Pro)

dbSNP: rs200252727

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165012	SCV000215707	likely benign	Hereditary cancer-predisposing syndrome	2018-06-19	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	RCV000196615	SCV000254406	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-18	criteria provided, single submitter	clinical testing
GeneDx	RCV000587565	SCV000617593	uncertain significance	not provided	2019-01-15	criteria provided, single submitter	clinical testing	This variant is denoted MSH2 c.2354A>C at the cDNA level, p.His785Pro (H785P) at the protein level, and results in the change of a Histidine to a Proline (CAT>CCT). This variant has been identified in at least one individual with a personal and family history of colorectal cancer, co-occurring with a POLD1 variant (Chubb 2015). MSH2 His785Pro was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Histidine and Proline differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH2 His785Pro occurs at a position that is conserved across species and is located in the ATPase domain (Lützen 2008, Kansikas 2011). 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 His785Pro is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000165012	SCV000685035	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-05	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with proline at codon 785 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 been reported in individuals affected with colorectal cancer (PMID: 25559809), breast cancer (PMID: 25186627) and kidney renal clear cell carcinoma (PMID: 29684080). This variant has been identified in 14/282842 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000522265	SCV000696245	uncertain significance	not specified	2021-03-19	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.2354A>C (p.His785Pro) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, C-terminal domain (IPR000432) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 251450 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MSH2 causing Hereditary Nonpolyposis Colorectal Cancer (4.8e-05 vs 0.00057), allowing no conclusion about variant significance. c.2354A>C has been reported in the literature in individuals affected with colon cancer and breast cancer (example, Chubb_2015, Tung_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer/Lynch syndrome. At-least one co-occurrence with another pathogenic variant has been reported (Chubb_2015, POLD1 c.1433G>A, p.Ser478Asn), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000522265	SCV000712626	uncertain significance	not specified	2016-11-17	criteria provided, single submitter	clinical testing	The p.His785Pro variant in MSH2 has been reported in 1 individual with colorecta l cancer; however, this patient also harbored a likely disease causing variant i n the POLD1 gene (Chubb et al 2015; POLD1, Ser478Asn: Palles 2013). The His785Pr o variant has been identified in 2/66730 European chromosomes by the Exome Aggre gation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs200252727). Com putational prediction tools and conservation analysis suggest that the p.His785P ro variant may impact the protein, though this information is not predictive eno ugh to determine pathogenicity. In summary, the clinical significance of the p.H is785Pro variant is uncertain.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587565	SCV001134353	uncertain significance	not provided	2020-09-30	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003462160	SCV004196326	uncertain significance	Lynch syndrome 1	2023-08-06	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003995381	SCV004825925	uncertain significance	Lynch syndrome	2024-01-11	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with proline at codon 785 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 been reported in individuals affected with colorectal cancer (PMID: 25559809), breast cancer (PMID: 25186627) and kidney renal clear cell carcinoma (PMID: 29684080). This variant has been identified in 14/282842 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.