Submissions for variant NM_002439.5(MSH3):c.1571A>C (p.Asn524Thr)

gnomAD frequency: 0.00220  dbSNP: rs55724159

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000966952	SCV001114312	benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000966952	SCV001159975	uncertain significance	not provided	2023-11-06	criteria provided, single submitter	clinical testing	The MSH3 c.1571A>C; p.Asn524Thr variant (rs55724159) is reported in the literature in a case of unselected colorectal cancer (DeRycke 2017). However, this variant is also found in the general population with an overall allele frequency of 0.07% (201/282046 alleles), with an increased frequency of 0.7% in the African population (Genome Aggregation Database). The asparagine at codon 524 is moderately conserved, but computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. However, due to limited information, the clinical significance of this variant is uncertain at this time. REFERENCES DeRycke MS et al. Targeted sequencing of 36 known or putative colorectal cancer susceptibility genes. Mol Genet Genomic Med. 2017 Jul 23;5(5):553-569.
Ambry Genetics	RCV001012233	SCV001172660	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.
Johns Hopkins Genomics, Johns Hopkins University	RCV001254630	SCV001430657	uncertain significance	Familial adenomatous polyposis 4	2020-06-26	criteria provided, single submitter	clinical testing	This MSH3 variant (rs55724159) is rare (<0.1%) in a large population dataset (gnomAD: 201/282046 total alleles; 0.071%; no homozygotes) with an increased frequency in individuals of African ancestry (0.7%). This variant has an entry in ClinVar and has been reported in a compound heterozygous state in a patient with unselected colorectal cancer. Three bioinformatic tools queried predict that p.Asn524Thr would be tolerated, and the asparagine residue at this position is mostly conserved across the species assessed. This variant is not predicted to affect normal exon 11 splicing, although this has not been confirmed experimentally to our knowledge. This variant alone is not likely to cause FAP4, but may represent a low-penetrance risk allele. Due to insufficient evidence, we consider the clinical significance of c.1571A>C to be uncertain at this time.
Baylor Genetics	RCV001254630	SCV001481257	uncertain significance	Familial adenomatous polyposis 4	2019-07-27	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001002124	SCV002047099	benign	not specified	2021-05-17	criteria provided, single submitter	clinical testing
GeneDx	RCV000966952	SCV002499981	uncertain significance	not provided	2022-02-14	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Identified in a patient with breast cancer (Faldoni 2020); This variant is associated with the following publications: (PMID: 33007869)
Sema4, Sema4	RCV001012233	SCV002535965	likely benign	Hereditary cancer-predisposing syndrome	2021-06-25	criteria provided, single submitter	curation
Mayo Clinic Laboratories, Mayo Clinic	RCV000966952	SCV002542125	uncertain significance	not provided	2022-01-07	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001002124	SCV004024352	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing