Submissions for variant NM_000251.3(MSH2):c.232G>A (p.Val78Ile)

gnomAD frequency: 0.00002  dbSNP: rs772779997

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000229561	SCV000284149	benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-11	criteria provided, single submitter	clinical testing
GeneDx	RCV000235910	SCV000292781	uncertain significance	not provided	2017-04-02	criteria provided, single submitter	clinical testing	This variant is denoted MSH2 c.232G>A at the cDNA level, p.Val78Ile (V78I) at the protein level, and results in the change of a Valine to an Isoleucine (GTT>ATT). This variant has been observed in one individual with non-medullary thyroid carcinoma (Yu 2015). MSH2 Val78Ile was not observed at a significant frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Valine and Isoleucine share similar properties, this is considered a conservative amino acid substitution. MSH2 Val78Ile occurs at a position that is conserved across species and is located within the mismatch binding domain (Lutzen 2008, Kansikas 2011). In silico analyses inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether MSH2 Val78Ile is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000491448	SCV000580552	benign	Hereditary cancer-predisposing syndrome	2021-11-15	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Color Diagnostics, LLC DBA Color Health	RCV000491448	SCV000685033	likely benign	Hereditary cancer-predisposing syndrome	2023-05-18	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003150133	SCV003838294	uncertain significance	Breast and/or ovarian cancer	2022-04-04	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003998761	SCV004832083	likely benign	Lynch syndrome	2023-06-08	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 78 of the MSH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least one individual each affected with colorectal cancer (PMID: 26900293), breast cancer (PMID: 28580595, 29752822), thyroid cancer (PMID: 26530882) and esophageal sarcomatoid carcinoma (PMID: 29506494). This variant has been identified in 9/245772 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.