Submissions for variant NM_000251.3(MSH2):c.2362A>C (p.Thr788Pro)

gnomAD frequency: 0.00002  dbSNP: rs774440277

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000585967	SCV000292626	uncertain significance	not provided	2023-03-20	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; Observed in individuals with breast or renal cancer and also in unaffected controls (Yehia et al., 2018; Dorling et al., 2021); Published functional studies suggest no damaging effect: performed similar to wild type in an assay measuring resistance to 6-TG (Jia et al., 2020); This variant is associated with the following publications: (PMID: 18822302, 21120944, 30029678, 33471991, 33357406, 29684080)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000456146	SCV000548216	likely benign	Hereditary nonpolyposis colorectal neoplasms	2025-01-21	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000569234	SCV000669733	uncertain significance	Hereditary cancer-predisposing syndrome	2024-04-23	criteria provided, single submitter	clinical testing	The p.T788P variant (also known as c.2362A>C), located in coding exon 14 of the MSH2 gene, results from an A to C substitution at nucleotide position 2362. The threonine at codon 788 is replaced by proline, 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 01;108:163-175). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000569234	SCV000685037	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-28	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with proline at codon 788 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 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 individuals affected with kidney renal cell carcinoma (PMID: 29684080). This variant has been identified in 3/282838 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001526856	SCV000696247	uncertain significance	not specified	2021-06-01	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.2362A>C (p.Thr788Pro) results in a non-conservative amino acid change located in the C-terminal domain (IPR000432) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251444 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, the variant, c.2362A>C, has not been reported in the literature in individuals affected with colorectal cancer or other tumor phenotypes that belong to the Lynch Syndrome tumor spectrum. On the other hand, the variant was reported in the literature in a patient affected with pulmonary arterial hypertension (Zhu_2018), and in multiple individuals affected with breast cancer, but also in in several healthy controls (Dorling_2021). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
CeGaT Center for Human Genetics Tuebingen	RCV000585967	SCV001152283	uncertain significance	not provided	2017-08-01	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001526856	SCV002552261	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003469179	SCV004194502	uncertain significance	Lynch syndrome 1	2024-01-06	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000585967	SCV004224907	uncertain significance	not provided	2022-07-19	criteria provided, single submitter	clinical testing	PP3, PM2
Clinical Genetics, Academic Medical Center	RCV000585967	SCV001918633	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000585967	SCV001957558	uncertain significance	not provided		no assertion criteria provided	clinical testing