Submissions for variant NM_000251.3(MSH2):c.1238A>C (p.Gln413Pro)

gnomAD frequency: 0.00004  dbSNP: rs587779962

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212601	SCV000149408	uncertain significance	not provided	2023-07-20	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 18822302, 21120944)
Ambry Genetics	RCV000115499	SCV000215745	uncertain significance	Hereditary cancer-predisposing syndrome	2025-01-22	criteria provided, single submitter	clinical testing	The p.Q413P variant (also known as c.1238A>C), located in coding exon 7 of the MSH2 gene, results from an A to C substitution at nucleotide position 1238. The glutamine at codon 413 is replaced by proline, an amino acid with similar properties. This variant was identified in a cohort of 3,579 African males diagnosed with prostate cancer who underwent multi-gene panel testing of 19 DNA repair and cancer predisposition genes (Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43). 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, 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.
Fulgent Genetics, Fulgent Genetics	RCV000515341	SCV000611400	uncertain significance	Lynch syndrome 1; Mismatch repair cancer syndrome 1; Muir-Torré syndrome	2017-05-23	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000532709	SCV000625241	benign	Hereditary nonpolyposis colorectal neoplasms	2024-11-06	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115499	SCV001359039	uncertain significance	Hereditary cancer-predisposing syndrome	2019-06-06	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115499	SCV002528824	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-22	criteria provided, single submitter	curation
Baylor Genetics	RCV003467045	SCV004196186	uncertain significance	Lynch syndrome 1	2023-10-16	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997269	SCV004832657	uncertain significance	Lynch syndrome	2024-07-20	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with proline at codon 413 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). This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). This variant has been reported in two individuals affected with prostate cancer (PMID: 32832836). This variant has been identified in 4/282628 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.
Myriad Genetics, Inc.	RCV003467045	SCV005899818	likely benign	Lynch syndrome 1	2024-12-06	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 27363726].