Submissions for variant NM_002439.5(MSH3):c.1567G>A (p.Glu523Lys)

gnomAD frequency: 0.00789  dbSNP: rs34058399

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000961622	SCV001108672	benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000961622	SCV001159790	likely benign	not provided	2023-11-06	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001012167	SCV001172590	likely benign	Hereditary cancer-predisposing syndrome	2018-10-01	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
GeneDx	RCV000961622	SCV002006995	likely benign	not provided	2021-06-21	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001800905	SCV002047098	benign	not specified	2021-05-17	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001800905	SCV002069770	benign	not specified	2021-10-25	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001800905	SCV002550492	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002479112	SCV002795553	likely benign	Endometrial carcinoma; Familial adenomatous polyposis 4	2021-11-24	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003960714	SCV004771967	benign	MSH3-related condition	2019-03-26	criteria provided, single submitter	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000961622	SCV001549254	uncertain significance	not provided		no assertion criteria provided	clinical testing	The MSH3 p.Glu523Lys variant was identified in the literature in 15 of 2462 proband chromosomes (frequency: 0.0061) from individuals with colorectal cancer (CRC) and was not identified in 186 control chromosomes from healthy individuals (DeRycke_2017_PMID: 28944238). The variant was also identified in dbSNP (ID: rs34058399) and LOVD 3.0. The variant was not identified in ClinVar, the Insight Colon Cancer Gene Variant Database, the Insight Hereditary Tumors Database or Cosmic. The variant was identified in control databases in 716 of 280904 chromosomes (7 homozygous) at a frequency of 0.002549 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 655 of 24526 chromosomes (freq: 0.02671), Latino in 42 of 35108 chromosomes (freq: 0.001196), Other in 6 of 7170 chromosomes (freq: 0.000837), European (non-Finnish) in 11 of 128728 chromosomes (freq: 0.000085) and South Asian in 2 of 30242 chromosomes (freq: 0.000066); it was not observed in the Ashkenazi Jewish, East Asian, and European (Finnish) populations. The variant was identified in a cohort of patients with colorectal cancer and controls without CRC, and classified as a variant of uncertain significance (DeRycke_2017_PMID: 28944238). The p.Glu523 residue is not conserved in mammals and five out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, and MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The p.Glu523Lys variant occurs in the second last base of the exon. This position has been shown to be part of the splicing consensus sequence and variants involving this position sometimes affect splicing. However, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, and GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.