Submissions for variant NM_000251.3(MSH2):c.2111T>C (p.Ile704Thr)

gnomAD frequency: 0.00001  dbSNP: rs564657106

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000222410	SCV000277734	likely benign	Hereditary cancer-predisposing syndrome	2023-04-14	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
Invitae	RCV000227730	SCV000284137	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-12-14	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 704 of the MSH2 protein (p.Ile704Thr). This variant is present in population databases (rs564657106, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of MSH2-related conditions (PMID: 23729658). ClinVar contains an entry for this variant (Variation ID: 233375). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33357406) indicates that this missense variant is not expected to disrupt MSH2 function with a negative predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect MSH2 function (PMID: 26951660). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Counsyl	RCV000411876	SCV000489282	uncertain significance	Lynch syndrome 1	2016-09-13	criteria provided, single submitter	clinical testing
GeneDx	RCV000483732	SCV000572481	uncertain significance	not provided	2018-01-19	criteria provided, single submitter	clinical testing	This variant is denoted MSH2 c.2111T>C at the cDNA level, p.Ile704Thr (I704T) at the protein level, and results in the change of an Isoleucine to a Threonine (ATT>ACT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Ile704Thr was not observed at a significant allele frequency in large population cohorts (Lek 2016). MSH2 Ile704Thr is located in the ATPase domain (Lutzen 2008, Kansikas 2011). In-silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MSH2 Ile704Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000222410	SCV000685012	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-27	criteria provided, single submitter	clinical testing
Mendelics	RCV000708841	SCV000837848	uncertain significance	Lynch syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000483732	SCV001470336	uncertain significance	not provided	2019-12-26	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000411876	SCV004018214	uncertain significance	Lynch syndrome 1	2023-03-16	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356541	SCV001551742	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The MSH2 p.Ile704Thr variant was identified in the literature however the frequency of this variant in an affected population was not provided (Houlleberghs 2016). The variant was also identified in dbSNP (ID: rs564657106) as "With Uncertain significance allele ", ClinVar (classified as uncertain significance by Ambry Genetics, Invitae, Counsyl, Genedx, Color Genomics), and in UMD-LSDB (2x as unclassified variant) databases. The variant was not identified in GeneInsight-COGR, Cosmic, MutDB, Zhejiang University Database, Mismatch Repair Genes Variant Database, and Insight Hereditary Tumors databases. The variant was identified in control databases in 2 of 246256 chromosomes at a frequency of 0.000008 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Latino in 1 of 33580 chromosomes (freq: 0.00003), European in 1 of 111706 chromosomes (freq: 0.000009), while the variant was not observed in the African, Other, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The variant does not disrupt MSH2 mismatch-repair activity and classified as undetected (Non-pathogenic) by oligonucleotide-directed mutagenesis screen by Houlleberghs (2016). The p.Ile704 residue is conserved in mammals but not in more distantly related 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, HumanSpliceFinder) 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. This variant is classified as a variant of uncertain significance.