Submissions for variant NM_000179.3(MSH6):c.3173-10_3173-6del

dbSNP: rs781520783

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001081009	SCV000254306	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2025-01-29	criteria provided, single submitter	clinical testing	This sequence change falls in intron 4 of the MSH6 gene. It does not directly change the encoded amino acid sequence of the MSH6 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or altered protein product. This variant is present in population databases (rs781520783, gnomAD 0.004%). This variant has been observed in individuals with Lynch syndrome (external communication, internal data). ClinVar contains an entry for this variant (Variation ID: 420284). Studies have shown that this variant results in activation of a cryptic splice site, and produces a non-functional protein and/or introduces a premature termination codon (internal data). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000483976	SCV000569055	likely pathogenic	not provided	2024-03-14	criteria provided, single submitter	clinical testing	Non-canonical splice variant demonstrated to result in aberrant splicing (External communication with Ambry Genetics and Invitae); Not observed at a significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge
Color Diagnostics, LLC DBA Color Health	RCV000580955	SCV000685361	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-09-29	criteria provided, single submitter	clinical testing	This variant causes a 5-basepair deletion in the polypyrimidine region in intron 4 of the MSH6 gene at the intron 4 splice acceptor site. Splice site prediction tools suggest that this variant may impact the splice acceptor site and result in aberrant RNA splicing. RNA studies have demonstrated this variant results in abnormal splicing (ClinVar SCV002610175.2, communication with Ambry Genetics). This variant has been reported in several individuals affected with Lynch syndrome (ClinVar SCV002610175.1). This variant has been identified in 1/251318 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH6 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Likely Pathogenic.
Counsyl	RCV000663016	SCV000786034	likely benign	Lynch syndrome 5	2018-02-08	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000580955	SCV002610175	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-06-04	criteria provided, single submitter	clinical testing	The c.3173-10_3173-6delCTTTT intronic variant, located in intron 4 of the MSH6 gene, results from a deletion of 5 nucleotides within intron 4 of the MSH6 gene. This variant has been identified in a proband(s) who met Amsterdam I/II criteria for Lynch syndrome and whose tumor demonstrated high microsatellite instability (Ambry internal data). This variant has also been identified in a proband(s) whose Lynch syndrome-associated tumor demonstrated loss of MSH6 expression by immunohistochemistry (Ambry internal data). These nucleotide positions are not well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may weaken the native splice acceptor site and may result in the creation or strengthening of a novel splice acceptor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Myriad Genetics, Inc.	RCV000663016	SCV004018458	uncertain significance	Lynch syndrome 5	2023-03-27	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
PreventionGenetics, part of Exact Sciences	RCV004535511	SCV004739015	likely benign	MSH6-related disorder	2019-05-22	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).