Submissions for variant NM_000179.3(MSH6):c.2964dup (p.Asn989fs)

dbSNP: rs587781659

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129802	SCV000184613	pathogenic	Hereditary cancer-predisposing syndrome	2024-06-05	criteria provided, single submitter	clinical testing	The c.2964dupC pathogenic mutation, located in coding exon 4 of the MSH6 gene, results from a duplication of C at nucleotide position 2964, causing a translational frameshift with a predicted alternate stop codon (p.N989Qfs*16). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
PreventionGenetics, part of Exact Sciences	RCV004528852	SCV004112050	pathogenic	MSH6-related disorder	2023-01-31	criteria provided, single submitter	clinical testing	The MSH6 c.2964dupC variant is predicted to result in a frameshift and premature protein termination (p.Asn989Glnfs*16). This variant has been reported in an individual with unknown phenotype (Table S3 in LaDuca et al. 2017. PubMed ID: 28152038). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. It is interpreted as pathogenic in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/141326/). Frameshift variants in MSH6 are expected to be pathogenic, and therefore we interpret c.2964dup (p.Asn989Glnfs*16) as pathogenic.
GeneDx	RCV003441749	SCV004169416	pathogenic	not provided	2023-05-09	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; Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Identified in individual(s) referred for hereditary cancer testing (LaDuca et al., 2017); This variant is associated with the following publications: (PMID: 28152038)
Myriad Genetics, Inc.	RCV003453069	SCV004185856	pathogenic	Lynch syndrome 5	2023-08-21	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.