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

Total submissions: 6

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 colorectal neoplasms	2019-08-15	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, ExAC 0.009%). This variant has not been reported in the literature in individuals with MSH2-related conditions. 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 and their clinical significance is uncertain. 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.
Ambry Genetics	RCV000574856	SCV000662267	uncertain significance	Hereditary cancer-predisposing syndrome	2019-04-30	criteria provided, single submitter	clinical testing	Insufficient evidence
Counsyl	RCV000663163	SCV000786321	uncertain significance	Lynch syndrome I	2018-04-06	criteria provided, single submitter	clinical testing
Color	RCV000574856	SCV001355751	uncertain significance	Hereditary cancer-predisposing syndrome	2019-06-06	criteria provided, single submitter	clinical testing
Integrated Genetics/Laboratory Corporation of America	RCV001193851	SCV001362999	uncertain significance	not specified	2019-04-09	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.1204C>A (p.Gln402Lys) results in a conservative amino acid change located in the DNA mismatch repair protein MutS, core domain (IPR007696) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.1e-05 in 277114 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1204C>A in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.