Submissions for variant NM_002439.5(MSH3):c.586del (p.Thr196fs)

dbSNP: rs771721952

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000797056	SCV000936595	pathogenic	not provided	2024-11-03	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Thr196Hisfs*37) in the MSH3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MSH3 are known to be pathogenic (PMID: 27476653, 37402566). This variant is present in population databases (rs771721952, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with MSH3-related conditions. ClinVar contains an entry for this variant (Variation ID: 643370). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002352334	SCV002650306	pathogenic	Hereditary cancer-predisposing syndrome	2023-06-16	criteria provided, single submitter	clinical testing	The c.586delA pathogenic mutation, located in coding exon 4 of the MSH3 gene, results from a deletion of one nucleotide at nucleotide position 586, causing a translational frameshift with a predicted alternate stop codon (p.T196Hfs*37). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
GeneDx	RCV000797056	SCV003923863	likely pathogenic	not provided	2023-12-20	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Has not been previously published as pathogenic or benign to our knowledge
Myriad Genetics, Inc.	RCV003458521	SCV004189060	pathogenic	Familial adenomatous polyposis 4	2023-08-29	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Baylor Genetics	RCV003467361	SCV004195149	likely pathogenic	Endometrial carcinoma	2024-01-03	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000797056	SCV005623849	likely pathogenic	not provided	2024-10-28	criteria provided, single submitter	clinical testing	The MSH3 c.586del (p.Thr196Hisfs*37) variant alters the translational reading frame of the MSH3 mRNA and is predicted to cause the premature termination of MSH3 protein synthesis. This variant has not been reported in individuals with MSH3-related conditions in the published literature. The frequency of this variant in the general population, 0.00025 (4/16216 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as likely pathogenic.