Submissions for variant NM_000251.3(MSH2):c.817G>A (p.Val273Ile)

gnomAD frequency: 0.00003  dbSNP: rs530814648

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000236426	SCV000293804	uncertain significance	not provided	2018-09-18	criteria provided, single submitter	clinical testing	This variant is denoted MSH2 c.817G>A at the cDNA level, p.Val273Ile (V273I) at the protein level, and results in the change of a Valine to an Isoleucine (GTA>ATA). MSH2 c.817G>A was observed, in unknown phase, with MSH2 c.818T>A in an individual with a colorectal tumor demonstrating microsatellite instability and loss of MSH2 protein expression (Pigatto 2004, Sharp 2004). Due to the affected bases being adjacent, if the variants are in cis, this would result in MSH2 Val273Lys, and if in trans, this individual would be compound heterozygous for MSH2 Val273Ile and Val273Glu. However, c.817G>A or another nucleotide substitution resulting in MSH2 Val273Ile alone has not, to our knowledge, been reported in the literature. MSH2 Val273Ile was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the connector domain (L?tzen 2008, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether MSH2 Val273Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae	RCV000458697	SCV000548233	benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-27	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000564711	SCV000676076	benign	Hereditary cancer-predisposing syndrome	2022-04-11	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Color Diagnostics, LLC DBA Color Health	RCV000564711	SCV000911234	likely benign	Hereditary cancer-predisposing syndrome	2016-08-12	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003998919	SCV004831466	likely benign	Lynch syndrome	2023-10-02	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356679	SCV001551917	likely benign	Endometrial carcinoma		no assertion criteria provided	clinical testing	The MSH2 p.Val273Ile variant was identified in dbSNP (ID: rs530814648) “With Uncertain significance allele”, ClinVar (classified uncertain significance by GeneDx, Invitae and Ambry Genetics), Clinvitae (2x), and not identified in GeneInsight-COGR, Cosmic, MutDB, UMD-LSDB, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, Insight Hereditary Tumors Database, databases. The variant was identified in control databases in 8 of 245604 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017), with breakdown of the observations by population include European Non-Finnish in 1 of 111478 chromosomes (freq: 0.000009) and South Asian in 7 of 30496 chromosomes (freq: 0.0002) while not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian and European Finnish, populations. The variant was also identified by our laboratory in 1 individual with endometrial cancer, co-occurring with a pathogenic MLH1 variant (c.588+1G>C). The p.Val273 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood the variant Ile impacts the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 3 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. RNA analysis (RT-PCR and allele specific RT-PCR) of peripheral blood RNA, on a cohort of patients with unclassified variants showed that the MSH2 c.817G>A;c.817T>A/p.Val274Lys was associated with normal RNA expression and splicing (Sharp_2004_ 15300854). 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 benign role for this variant. This variant is classified as likely benign.