Submissions for variant NM_000251.3(MSH2):c.1045C>A (p.Pro349Thr)

dbSNP: rs267607939

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000480250	SCV000572357	likely pathogenic	not provided	2016-11-28	criteria provided, single submitter	clinical testing	This variant is denoted MSH2 c.1045C>A at the cDNA level, p.Pro349Thr (P349T) at the protein level, and results in the change of a Proline to a Threonine (CCT>ACT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. However two other missense variants at the same residue (MSH2 Pro349Leu and Pro349Arg) have been reported in individuals with personal and family histories consistent with Lynch syndrome that are considered pathogenic by the International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT, Thompson 2014). MSH2 Pro349Thr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Proline and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH2 Pro349Thr occurs at a position that is conserved across species and is located in the Lever Domain (Lützen 2008, Kansikas 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the currently available evidence, we consider MSH2 Pro349Thr to be a likely pathogenic variant.
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003485590	SCV004239119	likely pathogenic	Lynch syndrome 1	2024-01-31	criteria provided, single submitter	clinical testing	This variant is denoted MSH2 p.Pro349Thr (P349T) at the protein level, and results in the change of a Proline to a Threonine .The p.Pro349 residue is conserved ( PhyloP=7.7). This variant reported in Clinvar database ( 422795) classified as likely pathogenic by two clinical laboratories. Moreover, two other missense variants at the same residue (MSH2 Pro349Leu and Pro349Arg) have been reported in individuals with personal and family histories consistent with Lynch syndrome . In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the currently available evidence, we consider MSH2 Pro349Thr to be a likely pathogenic variant. Pathogenic/likely pathogenic variants in the MSH2 gene cause Hereditary Non-Polyposis Colorectal Cancer Syndrome HNPCC (OMIM# 120435) also known as Lynch Syndrome. Lynch Syndrome is characterized by an increased risk for colorectal cancer (CRC) and cancers of the endometrium, ovary, stomach, small bowel, urinary tract, biliary tract, brain, skin (sebaceous adenomas, sebaceous carcinomas, and keratoacanthomas), pancreas, and prostate. Cancer risks and age of onset vary depending on the associated gene. Several other cancer types have been reported to occur in individuals with Lynch syndrome (e.g., breast, sarcomas, adrenocortical carcinoma).
Labcorp Genetics (formerly Invitae), Labcorp	RCV003766712	SCV004684996	likely pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-05-29	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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: 15342696, 21239990, 21926548, 24278394, 25117503, 25420488, 27606285). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 422795). This missense change has been observed in individual(s) with Lynch Syndrome and/or Lynch syndrome (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 349 of the MSH2 protein (p.Pro349Thr).
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355929	SCV001550957	likely pathogenic	Endometrial carcinoma		no assertion criteria provided	clinical testing	MSH2, EXON06, c.1045C>A, p.Pro349Thr, Heterozygous, Likely PathogenicrnThe MSH2 p.Pro349Thr variant was not identified in the literature nor was it identified in the dbSNP, COGR, Cosmic, MutDB, UMD-LSDB, Zhejiang University Database, Mismatch Repair Genes Variant Database, or Insight Hereditary Tumors databases. The variant was only identified in ClinVar database (classified as likely pathogenic by GeneDx). Please note, two other missense variants at the same residue (MSH2 Pro349Leu and Pro349Arg) have been reported in ClinVar as pathogenic. The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The p.Pro349 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic.