Submissions for variant NM_000251.3(MSH2):c.775C>T (p.Pro259Ser)

gnomAD frequency: 0.00001  dbSNP: rs587781294

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000128997	SCV000172892	likely benign	Hereditary cancer-predisposing syndrome	2023-03-16	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	RCV000228319	SCV000284183	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-19	criteria provided, single submitter	clinical testing
GeneDx	RCV000759122	SCV000292619	uncertain significance	not provided	2023-02-28	criteria provided, single submitter	clinical testing	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; Observed in individuals with Lynch-related and other cancers (Bonadona et al., 2011; Tung et al., 2016; Akcay et al., 2020); This variant is associated with the following publications: (PMID: 21642682, 12624141, 26976419, 31391288, 33471991, 21120944, 18822302, 33558524, 32658311, 31422574)
Color Diagnostics, LLC DBA Color Health	RCV000128997	SCV000685129	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-04	criteria provided, single submitter	clinical testing	This missense variant replaces proline with serine at codon 259 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 individuals affected with colorectal cancer (PMID: 32658311), breast cancer (PMID: 26976419, 32658311, 33558524), unspecified cancer (PMID: 31391288), and in individuals and families affected with Lynch syndrome (PMID: 12624141, 21642682). This variant has also been observed in healthy controls (PMID: 33471991) and in a healthy individual undergoing genetic testing for hereditary cancer (PMID: 31422574). This variant has been identified in 1/251078 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	RCV000759122	SCV000888232	uncertain significance	not provided	2022-12-09	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000004 (1/251078 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with Lynch syndrome (PMID: 21642682 (2011)), breast cancer (PMID: 26976419 (2016), 33558524 (2021), 32658311 (2021)), and colorectal cancer (PMID: 32658311 (2021)). The variant has also been reported in unaffected individuals (PMID: 33471991 (2021), 31422574 (2019)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000759122	SCV002009322	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000235651	SCV002556230	uncertain significance	not specified	2022-06-29	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.775C>T (p.Pro259Ser) results in a non-conservative amino acid change located in the connector domain (IPR007860) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251078 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.775C>T has been reported in the literature in individuals affected with colorectal cancer / (suspected) Lynch syndrome (e.g. Parc_2003, Bonadona_2011, Li_2020, Akcay_2020) and with breast cancer (e.g. Tung_2016, Akcay_2020, Moradian_2021), however, the variant was also found in healthy controls (Dorling_2021) and in cancer-free individuals undergoing whole-exome sequencing as a secondary finding (Kraemer_2019). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV004532540	SCV004107319	uncertain significance	MSH2-related disorder	2023-01-11	criteria provided, single submitter	clinical testing	The MSH2 c.775C>T variant is predicted to result in the amino acid substitution p.Pro259Ser. This variant has been reported as a variant of uncertain significance in patients with nonpolyposis colorectal cancer (eTable 1, Bonadona et al. 2011. PubMed ID: 21642682). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-47639682-C-T). This variant has been reported in ClinVar as uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/140810/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Baylor Genetics	RCV003333736	SCV004193918	uncertain significance	Lynch syndrome 1	2023-10-26	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997470	SCV004829160	uncertain significance	Lynch syndrome	2024-01-08	criteria provided, single submitter	clinical testing	This missense variant replaces proline with serine at codon 259 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 individuals affected with colorectal cancer (PMID: 32658311), breast cancer (PMID: 26976419, 32658311, 33558524), unspecified cancer (PMID: 31391288), and in individuals and families affected with Lynch syndrome (PMID: 12624141, 21642682). This variant has also been observed in healthy controls (PMID: 33471991) and in a healthy individual undergoing genetic testing for hereditary cancer (PMID: 31422574). This variant has been identified in 1/251078 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.
Center of Medical Genetics and Primary Health Care	RCV001269353	SCV001448696	uncertain significance	Malignant tumor of breast	2020-09-01	no assertion criteria provided	clinical testing
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	RCV003333736	SCV004041656	uncertain significance	Lynch syndrome 1	2023-10-09	no assertion criteria provided	clinical testing