Submissions for variant NM_000251.3(MSH2):c.797C>T (p.Ala266Val)

dbSNP: rs587781745

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129950	SCV000184773	uncertain significance	Hereditary cancer-predisposing syndrome	2022-06-30	criteria provided, single submitter	clinical testing	The p.A266V variant (also known as c.797C>T), located in coding exon 5 of the MSH2 gene, results from a C to T substitution at nucleotide position 797. The alanine at codon 266 is replaced by valine, an amino acid with similar properties. This alteration was identified in a cohort of 1260 individuals undergoing panel testing for Lynch syndrome due to having a diagnosis of a Lynch-associated cancer and/or polyps (Yurgelun MB et al. Gastroenterology, 2015 Sep;149:604-13.e20). This alteration has also been identified in a cohort of Israeli subjects with personal and/or family history suspicious for Lynch syndrome (Goldberg Y et al. Clin. Genet., 2015 Jun;87:549-53). In a massively parallel cell-based functional assay testing susceptibility to a DNA damaging agent, 6-thioguanine (6-TG), this variant was reported to be functionally neutral (Jia X et al. Am J Hum Genet, 2021 01;108:163-175). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000212590	SCV000211167	uncertain significance	not provided	2016-08-24	criteria provided, single submitter	clinical testing	This variant is denoted MSH2 c.797C>T at the cDNA level, p.Ala266Val (A266V) at the protein level, and results in the change of an Alanine to a Valine (GCA>GTA). This variant has been observed in at least two individuals suspected of having Lynch syndrome due to personal and/or family history (Goldberg 2014, Yurgelun 2015). MSH2 Ala266Val 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 Alanine and Valine share similar properties, this is considered a conservative amino acid substitution. MSH2 Ala266Val occurs at a position that is conserved across species and is located in the Connector domain (Lutzen 2008). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether MSH2 Ala266Val is pathogenic or benign. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000630072	SCV000751028	likely pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-10-08	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 266 of the MSH2 protein (p.Ala266Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Lynch syndrome (PMID: 25430799, 25980754; Invitae; external communication). ClinVar contains an entry for this variant (Variation ID: 141437). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33357406) did not meet the statistical confidence thresholds required to predict the impact of this variant on MSH2 function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.