Submissions for variant NM_000251.3(MSH2):c.517C>G (p.Leu173Val)

gnomAD frequency: 0.00001  dbSNP: rs1176822890

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001023669	SCV001185581	uncertain significance	Hereditary cancer-predisposing syndrome	2024-02-15	criteria provided, single submitter	clinical testing	The p.L173V variant (also known as c.517C>G), located in coding exon 3 of the MSH2 gene, results from a C to G substitution at nucleotide position 517. The leucine at codon 173 is replaced by valine, an amino acid with highly similar properties. 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 Jan;108:163-175). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear.
Invitae	RCV001323361	SCV001514273	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-05-23	criteria provided, single submitter	clinical testing	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. This variant disrupts the p.Leu173 amino acid residue in MSH2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15849733, 16395668, 17101317, 18383312, 23741719). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33357406) indicates that this missense variant is not expected to disrupt MSH2 function. ClinVar contains an entry for this variant (Variation ID: 825511). This variant has not been reported in the literature in individuals affected with MSH2-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 173 of the MSH2 protein (p.Leu173Val).
Sema4, Sema4	RCV001023669	SCV002534530	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-18	criteria provided, single submitter	curation
Baylor Genetics	RCV003467676	SCV004196210	uncertain significance	Lynch syndrome 1	2023-10-05	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001023669	SCV004356603	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-12	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with valine at codon 173 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 not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 2/251484 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.
All of Us Research Program, National Institutes of Health	RCV004004639	SCV004828388	uncertain significance	Lynch syndrome	2023-10-30	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with valine at codon 173 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 not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 2/251484 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.