Submissions for variant NM_000251.3(MSH2):c.1046C>T (p.Pro349Leu)

dbSNP: rs587779067

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076009	SCV000107020	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Multifactorial likelihood analysis posterior probability >0.99
Ambry Genetics	RCV000217955	SCV000278096	pathogenic	Hereditary cancer-predisposing syndrome	2022-08-09	criteria provided, single submitter	clinical testing	The p.P349L pathogenic mutation (also known as c.1046C>T), located in coding exon 6 of the MSH2 gene, results from a C to T substitution at nucleotide position 1046. The proline at codon 349 is replaced by leucine, an amino acid with similar properties. This alteration was first reported in an individual diagnosed with multiple Lynch syndrome (LS)-associated cancers, from a family meeting Amsterdam II criteria, who tested negative for the BRAF-V600E mutation (Domingo E et al. J. Med. Genet. 2004 Sep;41:664-8). Further analysis of this family showed that this alteration segregated with family members affected with LS-associated cancers (Lindor NM et al. Pancreas. 2011 Oct;40:1138-40). This mutation also segregates with disease in two families tested by our laboratory (Ambry internal data). This mutation was more recently identified in a man diagnosed with prostate cancer at age 47, whose family met Amsterdam II criteria (Rosty C et al. Fam. Cancer. 2014 Dec;13:573-82) and has been classified as pathogenic using the following lines of evidence: in silico prediction models, segregation with disease, clinical phenotype including tumor characteristics, mutation co-occurrence, and functional studies (Thompson BA et al. Hum. Mutat. 2013 Jan;34:200-9; Thompson BA et al. Nat. Genet. 2014 Feb;46:107-15; available at [www.insight-group.org/variants/classifications/]). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species and is located in the highly conserved lever domain of the MSH2 protein that mediates signals between the ATP- and DNA-binding activities of MSH2. Studies of other alterations in this domain have been shown to negatively impact protein stability and showed loss of protein on tumor staining (Gammie AE et al. Genetics. 2007 Oct;177:707-21; Ollila S et al. Hum. Mutat. 2008 Nov;29:1355-63). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000508278	SCV000601423	likely pathogenic	not provided	2017-03-08	criteria provided, single submitter	clinical testing
Invitae	RCV000694503	SCV000822952	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-11-01	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 349 of the MSH2 protein (p.Pro349Leu). 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: 15342696, 21926548, 25117503, 25420488). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 90514). 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: 26951660). This variant disrupts the p.Pro349 amino acid residue in MSH2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21239990, 24278394, 26951660, 27606285). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc.	RCV003452797	SCV004186693	likely pathogenic	Lynch syndrome 1	2023-07-31	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant is expected to disrupt protein structure [Myriad internal data]. Functional studies indicate this variant impacts protein function [PMID: 26951660]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 21926548, 25117503].
Baylor Genetics	RCV003452797	SCV004196879	pathogenic	Lynch syndrome 1	2022-12-05	criteria provided, single submitter	clinical testing