ClinVar Miner

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

gnomAD frequency: 0.00006  dbSNP: rs587779965
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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212611 SCV000149421 uncertain significance not provided 2022-04-07 criteria provided, single submitter clinical testing Observed in individuals with colon and other cancers (Yurgelun 2015, Zhang 2015, DeRycke 2017, Raskin 2017, Yurgelun 2017, Zidan 2017, Buckley 2018, Germani 2020, Zhu 2020); 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: 23729658, 32957588, 26046367, 25980754, 26580448, 28526081, 28828701, 28944238, 28135145, 29212164, 30217226, 32090079, 31265121)
Ambry Genetics RCV000115512 SCV000172808 benign Hereditary cancer-predisposing syndrome 2021-04-15 criteria provided, single submitter clinical testing The p.P616R variant (also known as c.1847C>G), located in coding exon 12 of the MSH2 gene, results from a C to G substitution at nucleotide position 1847. The proline at codon 616 is replaced by arginine, an amino acid with dissimilar properties. This variant was identified in two pediatric patients with ALL (Zhang J et al. N. Engl. J. Med. 2015 Dec;373:2336-2346) and in a cohort of 1260 individuals undergoing panel testing for Lynch syndrome due to having a diagnosis of a Lynch-associated cancer and/or polyps (Yurgelun MB et al. Gastroenterology. 2015 Sep;149:604-13.e20). This alteration was also reported in an individual with microsatellite stable (MSS) colorectal cancer diagnosed at 57; immunohistochemistry (IHC) of this tumor demonstrated intact staining of the mismatch repair proteins (Raskin L et al. Oncotarget. 2017 Nov;8:93450-93463). This variant has also been identified in several probands whose Lynch-associated tumors were MSS and/or demonstrated intact staining of the mismatch repair proteins on IHC (Ambry internal data). In a massively parallel cell-based functional assay testing susceptibility to a DNA damaging agent, 6-thioguanine (6-TG), this variant was determined to be functionally neutral (Jia X et al. Am J Hum Genet, 2021 Jan;108:163-175). Based on data from gnomAD, the G allele has an overall frequency of 0.0067% (19/282854) total alleles studied. The highest observed frequency of 0.031% (11/35438) alleles in the Latino population is above the maximum credible frequency for a disease-causing variant in this gene based on internally established thresholds (Karczewski et al. Nature. 2020 May;581(7809):434-443; Whiffin et al. Genet Med, 2017 10;19:1151-1158). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is interpreted as a benign polymorphism.
Invitae RCV000205979 SCV000260268 likely benign Hereditary nonpolyposis colorectal neoplasms 2021-12-17 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
PreventionGenetics,PreventionGenetics RCV000212611 SCV000806014 uncertain significance not provided 2017-01-10 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 2020-07-23 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001194001 SCV001363217 likely benign not specified 2021-08-02 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. 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. Eight 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, n=2, VUS n=6). 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
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.

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