Submissions for variant NM_000251.3(MSH2):c.1847C>G (p.Pro616Arg)

gnomAD frequency: 0.00003  dbSNP: rs587779965

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212611	SCV000149421	uncertain significance	not provided	2023-12-21	criteria provided, single submitter	clinical testing	Observed in individuals with colon, breast, or other cancers (PMID: 25980754, 26580448, 28944238, 29212164, 28135145, 28828701, 30217226, 32957588, 31265121, 33471991); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies suggest a neutral effect: mismatch repair activity comparable to wild-type (PMID: 33357406); This variant is associated with the following publications: (PMID: 23729658, 32957588, 26046367, 25980754, 26580448, 28526081, 28828701, 28944238, 28135145, 29212164, 30217226, 32090079, 31265121, 9774676, 18822302, 18822303, 21120944, 33471991, 34326862, 33357406)
Ambry Genetics	RCV000115512	SCV000172808	benign	Hereditary cancer-predisposing syndrome	2021-04-15	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000205979	SCV000260268	likely benign	Hereditary nonpolyposis colorectal neoplasms	2025-01-08	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115512	SCV000292216	likely benign	Hereditary cancer-predisposing syndrome	2020-05-11	criteria provided, single submitter	clinical testing
Counsyl	RCV000411841	SCV000489511	uncertain significance	Lynch syndrome 1	2016-10-18	criteria provided, single submitter	clinical testing
Mendelics	RCV000708836	SCV000837841	uncertain significance	Lynch syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212611	SCV001134346	uncertain significance	not provided	2023-08-08	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in an individual affected with a Lynch syndrome–associated cancer and/or polyps (PMID: 25980754 (2015)), colorectal cancer (PMIDs: 28135145 (2017), 28944238 (2017), 29212164 (2017)), breast/ovarian cancer (PMIDs: 28828701 (2017), 31265121 (2020), 32957588 (2020)), and acute lymphoblastic leukemia (PMID: 26580448 (2015)). The results from one indirect functional study indicated that this variant likely retains DNA mismatch repair activity in HAP1 cells, while discordant results were observed in a different cell line (PMID: 33357406 (2021)). The frequency of this variant in the general population, 0.00031 (11/35438 chromosomes in Latino/Admixed American subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001194001	SCV001363217	likely benign	not specified	2023-01-06	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.1847C>G (p.Pro616Arg) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, core (IPR007696) domain of the encoded protein sequence. Three of three in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.8e-05 in 251478 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MSH2 causing Hereditary Nonpolyposis Colorectal Cancer (6.8e-05 vs 0.00057), allowing no conclusion about variant significance. c.1847C>G has been reported in the literature in patients with colorectal cancer and other cancer phenotypes (examples: Raskin_2017, Yurgelun_2017, DeRychke_2017, etc). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. Co-occurrences with other pathogenic variants have been reported (MSH2 large deletion, Cheng_2017; RAD51C c.934C>T, p.Arg312Trp, Germani_2020), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign/benign, n=3, VUS n=7). Based on the evidence outlined above, the variant was classified as likely benign.
Genetic Services Laboratory, University of Chicago	RCV001194001	SCV002069934	uncertain significance	not specified	2019-11-26	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115512	SCV002534415	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-12	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000411841	SCV004018333	benign	Lynch syndrome 1	2024-12-11	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 27363726]. Homozygosity for this variant has been confirmed in one or more individuals lacking clinical features consistent with gene-specific recessive disease, indicating that this variant is unlikely to be pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000212611	SCV004564598	likely benign	not provided	2023-11-20	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004734650	SCV000806014	uncertain significance	MSH2-related disorder	2024-07-05	no assertion criteria provided	clinical testing	The MSH2 c.1847C>G variant is predicted to result in the amino acid substitution p.Pro616Arg. This variant has been reported in individuals with colorectal cancer and/or suspected Lynch syndrome (Yurgelun et al. 2017. PubMed ID: 28135145; Raskin et al. 2017. PubMed ID: 29212164; Table S2, Yurgelun et al. 2015. PubMed ID: 25980754; Table S4a, Zhang et al. 2015. PubMed ID: 26580448). This variant is reported in 0.031% of alleles in individuals of Latino descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/127636/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355718	SCV001550675	uncertain significance	Carcinoma of colon		no assertion criteria provided	clinical testing	The MSH2 p.Pro616Arg variant was identified in 4 of 5226 proband chromosomes (frequency: 0.001; Cheng 2015, Yurgelun 2015, Zhang 2015) with Lynch syndrome-related cancers or colorectal polyps. The variant was identified in dbSNP (ID: rs587779965 as With Uncertain significance allele), ClinVar (5x as a variant of uncertain significance), and UMD-LSDB (1x). The variant was identified in control databases in 17 of 277206 chromosomes at a frequency of 0.00006 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include: African in 1 of 24034 chromosomes (freq: 0.00004), Latino in 12 of 34418 chromosomes (freq: 0.0003), and European Non-Finnish in 4 of 126704 chromosomes (freq: 0.00003), while the variant was not observed in the Other, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Pro616 residue is well conserved in mammals and other organisms and 5 of 5 computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the p.Pro616Arg variant may impact the protein; however, this information is not reliably predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 5 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information, clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.