Submissions for variant NM_000251.2(MSH2):c.1204C>A (p.Gln402Lys) (rs63751412)

Minimum review status:		Collection method:
Minimum conflict level:
		ClinVar version:

Total submissions: 4

Download table as spreadsheet

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000115497	SCV000149406	uncertain significance	not provided	2015-02-28	criteria provided, single submitter	clinical testing	This variant is denoted MSH2 c.1204C>A at the cDNA level, p.Gln402Lys (Q402K) at the protein level, and results in the change of a Glutamine to a Lysine (CAA>AAA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Gln402Lys was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Glutamine and Lysine differ in some properties, this is considered a semi-conservative amino acid substitution and may affect protein integrity. MSH2 Gln402Lys occurs at a position that is well conserved across species and is located in the Lever domain (Lutzen 2008). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether MSH2 Gln402Lys is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae	RCV000206195	SCV000260627	uncertain significance	Hereditary nonpolyposis colon cancer	2018-06-03	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine with lysine at codon 402 of the MSH2 protein (p.Gln402Lys). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and lysine. This variant is present in population databases (rs63751412, 0.009%) but has not been reported in the literature. ClinVar contains an entry for this variant (Variation ID: 127628). 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 disruptive, but these predictions have not been confirmed by published functional studies. In summary, this is a rare missense change with uncertain impact on protein function. There is no indication that this variant causes disease, but the evidence is insufficient at this time to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV000574856	SCV000662267	uncertain significance	Hereditary cancer-predisposing syndrome	2017-02-10	criteria provided, single submitter	clinical testing	Lines of evidence used in support of classification: Insufficient evidence
Counsyl	RCV000663163	SCV000786321	uncertain significance	Lynch syndrome I	2018-04-06	criteria provided, single submitter	clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.