Submissions for variant NM_000251.3(MSH2):c.2725A>C (p.Lys909Gln)

dbSNP: rs879254253

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000236832	SCV000293973	uncertain significance	not provided	2016-02-16	criteria provided, single submitter	clinical testing	This variant is denoted MSH2 c.2725A>C at the cDNA level, p.Lys909Gln (K909Q) at the protein level, and results in the change of a Lysine to a Glutamine (AAA>CAA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Lys909Gln 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 Lysine and Glutamine differ in some properties, this is considered a semi-conservative amino acid substitution. MSH2 Lys909Gln occurs at a position where amino acids with properties similar to Lysine are tolerated across species and is located in the helix-turn-helix domain (Lützen 2008). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether MSH2 Lys909Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000812576	SCV000952894	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2018-12-04	criteria provided, single submitter	clinical testing	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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with MSH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 246423). This variant is not present in population databases (ExAC no frequency). This sequence change replaces lysine with glutamine at codon 909 of the MSH2 protein (p.Lys909Gln). The lysine residue is weakly conserved and there is a small physicochemical difference between lysine and glutamine.
PreventionGenetics, part of Exact Sciences	RCV004532986	SCV004121664	uncertain significance	MSH2-related disorder	2022-10-05	criteria provided, single submitter	clinical testing	The MSH2 c.2725A>C variant is predicted to result in the amino acid substitution p.Lys909Gln. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/246423/?new_evidence=false). A different substitution affecting the same amino acid (p.Lys909Arg) has been reported in patients with colorectal cancer (Yurgelun et al. 2017. PubMed ID: 28135145 ). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.