Submissions for variant NM_000251.3(MSH2):c.100G>A (p.Val34Met)

gnomAD frequency: 0.00001  dbSNP: rs1064793541

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000484906	SCV000566373	uncertain significance	not provided	2015-04-23	criteria provided, single submitter	clinical testing	This variant is denoted MSH2 c.100G>A at the cDNA level, p.Val34Met (V34M) at the protein level, and results in the change of a Valine to a Methionine (GTG>ATG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Val34Met 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 Valine and Methionine share similar properties, this is considered a conservative amino acid substitution. MSH2 Val34Met occurs at a position that is conserved through mammals and is located in the mismatch binding 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 Val34Met is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV001016981	SCV001177997	likely benign	Hereditary cancer-predisposing syndrome	2021-09-30	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
Invitae	RCV001037181	SCV001200582	likely benign	Hereditary nonpolyposis colorectal neoplasms	2023-12-19	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001016981	SCV001354723	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-15	criteria provided, single submitter	clinical testing	This missense variant replaces valine with methionine at codon 34 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). This variant has intermediate MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold -1.32 < LOF score < 0.88, PMID: 33357406). In a pancreatic cancer case-control study, this variant has been reported in 0/1005 pancreatic cancer cases and 13/23705 controls (PMID: 32980694). This variant has been identified in 2/223268 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000484906	SCV001469547	uncertain significance	not provided	2020-06-25	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004002277	SCV004828859	uncertain significance	Lynch syndrome	2023-04-03	criteria provided, single submitter	clinical testing	This missense variant replaces valine with methionine at codon 34 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). This variant has intermediate MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold -1.32 < LOF score < 0.88, PMID: 33357406). This variant has been reported in a pancreatic cancer case-control study as present in 13 unaffected individuals and absent in cancer cases (PMID: 32980694). This variant has been identified in 2/223268 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.