Submissions for variant NM_000251.3(MSH2):c.1397A>G (p.His466Arg)

gnomAD frequency: 0.00001  dbSNP: rs544265737

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000463668	SCV000548254	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-16	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000561959	SCV000664625	uncertain significance	Hereditary cancer-predisposing syndrome	2021-04-20	criteria provided, single submitter	clinical testing	The p.H466R variant (also known as c.1397A>G), located in coding exon 9 of the MSH2 gene, results from an A to G substitution at nucleotide position 1397. The histidine at codon 466 is replaced by arginine, an amino acid with highly similar properties. This alteration has been reported in a patient with rectal and uterine cancer at age 40 from a cohort of 1,046 familial colorectal cancer cases (Raskin L et al. Oncotarget, 2017 Nov;8:93450-93463). This variant was also reported in 1/60,466 breast cancer cases and in 1/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). 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.
Color Diagnostics, LLC DBA Color Health	RCV000561959	SCV001353705	uncertain significance	Hereditary cancer-predisposing syndrome	2022-06-21	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with arginine at codon 466 of the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with colorectal and uterine cancer in the literature (PMID: 29212164). This variant has been identified in 9/251244 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.
GeneDx	RCV001753886	SCV001988389	uncertain significance	not provided	2020-02-24	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with a personal history of colorectal cancer (Raskin 2017); This variant is associated with the following publications: (PMID: 29212164, 31569399)
All of Us Research Program, National Institutes of Health	RCV004000788	SCV004833263	uncertain significance	Lynch syndrome	2023-06-08	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with arginine at codon 466 of the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with colorectal and uterine cancer in the literature (PMID: 29212164). This variant has been identified in 9/251244 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.