Submissions for variant NM_000251.3(MSH2):c.2266_2267insAGA (p.Ser755_Thr756insLys)

dbSNP: rs1553369686

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000573846	SCV000676098	uncertain significance	Hereditary cancer-predisposing syndrome	2020-03-31	criteria provided, single submitter	clinical testing	The c.2266_2267insAGA variant (also known as p.S755_T756insK), located in coding exon 14 of the MSH2 gene, results from an in-frame AGA insertion at nucleotide positions 2266 to 2267. This results in the insertion of an extra lysine residue between codons 755 and 756. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV005091076	SCV005739331	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-02-04	criteria provided, single submitter	clinical testing	This variant, c.2266_2267insAGA, results in the insertion of 1 amino acid(s) of the MSH2 protein (p.Ser755_Thr756insLys), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MSH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 433900). 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000504395	SCV000592547	uncertain significance	Carcinoma of colon		no assertion criteria provided	clinical testing	The MSH2 p.Ser755_Thr756insLys variant was not identified in the literature nor was it identified in the in dbSNP, 1000 Genomes Project, NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium database (August 8, 2016), Clinvitae, COSMIC, Mismatch Repair Genes Variant, MMR Gene Unclassified Variants, InSiGHT Colon Cancer Gene Variant (LOVD), Zhejiang Colon Cancer Database (LOVD), ClinVar database, GeneInsight - COGR database, and UMD databases. The variant occurs outside of the splicing consensus sequence and 4 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. This variant is an in-frame insertion resulting in the addition of Lys residue at codon 755_756; the impact of this alteration on MSH2 protein function is not known. 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.