Submissions for variant NM_000179.3(MSH6):c.3G>T (p.Met1Ile)

dbSNP: rs876660095

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000680209	SCV000807674	likely pathogenic	Lynch syndrome	2019-06-21	reviewed by expert panel	curation	Variant in the initiation codon of MSH6
Ambry Genetics	RCV000219646	SCV000277232	pathogenic	Hereditary cancer-predisposing syndrome	2021-04-30	criteria provided, single submitter	clinical testing	The p.M1? pathogenic mutation (also known as c.3G>T) is located in exon 1 of the MSH6 gene and results from a G to T substitution at nucleotide position 3. This alters the methionine residue at the initiation codon (ATG). This mutation has been identified in multiple individuals meeting Amsterdam criteria and/or whose tumors demonstrated absent MSH6 staining on IHC (Ambry internal data). In addition, this mutation was seen in trans with a likely pathogenic variant in MSH6 in an individual with constitutional mismatch repair deficiency (CMMRD) confirmed by abnormal IHC in both tumor and normal tissue (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Sequence variations that modify the initiation codon are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
GeneDx	RCV000485238	SCV000568008	likely pathogenic	not provided	2023-09-18	criteria provided, single submitter	clinical testing	Initiation codon variant in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (LaDuca et al., 2017); This variant is associated with the following publications: (PMID: 28152038)
Invitae	RCV000793054	SCV000932389	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-08-31	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 232954). Disruption of the initiator codon has been observed in individuals with clinical features of Lynch syndrome (PMID: 21520333; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the MSH6 mRNA. The next in-frame methionine is located at codon 100.