Submissions for variant NM_000251.3(MSH2):c.1571G>C (p.Arg524Pro)

dbSNP: rs63751207

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076197	SCV000107214	likely pathogenic	Lynch syndrome	2019-06-21	reviewed by expert panel	curation	Abrogated function & 2 MSI-H tumours
Ambry Genetics	RCV000165648	SCV000216385	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-08-22	criteria provided, single submitter	clinical testing	The p.R524P variant (also known as c.1571G>C), located in coding exon 10 of the MSH2 gene, results from a G to C substitution at nucleotide position 1571. The arginine at codon 524 is replaced by proline, an amino acid with dissimilar properties. This alteration was first reported in an individual diagnosed at age 38 with a microsatellite instability high ovarian cancer with loss of heterozygosity (Orth K et al. Proc. Natl. Acad. Sci. U.S.A. 1994 Sep; 91(20):9495-9). This alteration has also been reported in an individual with the Muir-Torre variant of Lynch syndrome and an individual meeting Bethesda criteria (Mangold E et al. J. Med. Genet. 2004 Jul; 41(7):567-72; Shirts BH et al. Genet Med. 2016 Oct;18(10):974-81). This alteration is located in the clamp domain and in vitro DNA binding, ATPase and sliding clamp dissociation studies have shown an effect on the mismatch-dependent molecular switch function of the hMSH2-hMSH6 heterodimer (Heinen CD et al. Cancer Cell 2002 Jun; 1(5):469-78). Multiple functional assays have demonstrated that this protein was repair-deficient, unstable, and unable to elicit a DNA checkpoint in response to DNA alkylation damage (Boyer JC et al. Cancer Res. 1995 Dec; 55(24):6063-70; Mastrocola AS et al. Hum. Mutat. 2010 Oct; 31(10):E1699-708; Nielsen SV et al. PLoS Genet. 2017 Apr 19;13(4):e1006739). In addition, in a massively parallel cell-based functional assay testing susceptibility to a DNA damaging agent, 6-thioguanine (6-TG), this variant was reported to be functionally deleterious (Jia X et al. Am J Hum Genet, 2021 01;108:163-175). This amino acid position is highly conserved in available vertebrate species, and the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000076197	SCV000266080	likely pathogenic	Lynch syndrome	2015-11-20	criteria provided, single submitter	clinical testing
GeneDx	RCV000256140	SCV000322357	likely pathogenic	not provided	2021-03-23	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: defective mismatch repair, abolishment of the dominant mutator phenotype, deficient ATPase activity, reduced mismatch-binding in vitro and MNNG-induced chromatin-binding in cells, and decreased MMR protein complex assembly (Boyer 1995, Guerrette 1998, Clark 1999, Drotschmann 1999, Heinen 2002, Mastrocola 2010, Jia 2020); Observed in patients with Lynch-related cancers and tumor studies consistent with pathogenic variants in this gene (Mangold 2004, Roberts 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 16995940, 14526391, 23741719, 16327991, 28422960, 20672385, 22290698, 7937795, 8521394, 18383312, 12124176, 9889267, 10469597, 17720936, 9774676, 15340264, 15235030, 17074586, 17594722, 24362816, 16321766, 19062740, 26078562, 21665242, 29345684, 28125613, 12760035, 33357406)
Invitae	RCV000531855	SCV000625286	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-12-12	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 524 of the MSH2 protein (p.Arg524Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 7937795, 15235030, 15849733, 18931482, 26845104; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1759). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33357406) indicates that this missense variant is expected to disrupt MSH2 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects MSH2 function (PMID: 7937795, 10469597, 17594722, 20672385). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000165648	SCV000684947	likely pathogenic	Hereditary cancer-predisposing syndrome	2020-08-31	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with proline at codon 524 in the MSH3/MSH6 interaction and clamp domain of the MSH2 protein. Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold ‚â•0.7, PMID: 27666373). Functional studies have shown that this variant reduces interactions with MSH3 or MSH6 and impairs mismatch repair (MMR) activities (PMID: 8521394, 12124176, 17594722, 20672385). This variant has been reported in individuals with or suspected with Lynch syndrome (PMID: 15849733, 18931482) and in one individual affected with colorectal cancer (PMID: 26845104). This variant has also been reported in one individual with Muir-Torre syndrome (PMID: 15235030). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
CSER _CC_NCGL, University of Washington	RCV000076197	SCV000700092	likely pathogenic	Lynch syndrome	2016-10-01	criteria provided, single submitter	research	Found in patient having exome sequencing due to suspicion for hereditary colon cancer and/or polyps. Patient is a 37 year old female diagnosed with colon cancer at age 36. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000256140	SCV000889416	likely pathogenic	not provided	2018-04-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001251063	SCV000919690	likely pathogenic	Hereditary nonpolyposis colon cancer	2020-07-29	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.1571G>C (p.Arg524Pro) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, clamp (IPR007861) and DNA mismatch repair protein MutS, core (IPR007696) domains of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251380 control chromosomes. c.1571G>C has been reported in the literature in individuals affected with Muir-Torre syndrome (e.g. Mangold_2004), ovarian cancer (e.g. Orth_1994), and colon cancer (e.g. Shirts_2016). These data indicate that the variant may be associated with disease. Several publications report experimental evidence evaluating an impact on protein function (e.g. Drotschmann_1999, Heinen_2002, Gammie_2007, Mastrocola_2010). The most pronounced variant effect results in <10% of normal activity. Eight other 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 pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Myriad Genetics, Inc.	RCV000001829	SCV004186687	likely pathogenic	Lynch syndrome 1	2023-08-02	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 12124176, 20672385, 28422960]. This variant is expected to disrupt protein structure [Myriad internal data].
OMIM	RCV000001829	SCV000021985	pathogenic	Lynch syndrome 1	1994-09-27	no assertion criteria provided	literature only