Submissions for variant NM_000179.3(MSH6):c.1634_1637del (p.Lys545fs)

dbSNP: rs63749874

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000074674	SCV000107877	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
GeneDx	RCV000497289	SCV000149287	pathogenic	not provided	2022-12-20	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; Identified in patients with Lynch syndrome in published literature (Arnold et al., 2007; Kidambi et al., 2017); 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; This variant is associated with the following publications: (PMID: 17323113, 28152038, 29345684, 30787465, 34930662, 28514183, 28283864)
Ambry Genetics	RCV000115378	SCV000214467	pathogenic	Hereditary cancer-predisposing syndrome	2021-04-19	criteria provided, single submitter	clinical testing	The c.1634_1637delAAGA pathogenic mutation, located in coding exon 4 of the MSH6 gene, results from a deletion of 4 nucleotides at nucleotide positions 1634 to 1637, causing a translational frameshift with a predicted alternate stop codon (p.K545Rfs*25). This mutation has been detected in two unrelated families whose history is suggestive of Lynch syndrome. In both of these families, immunohistochemistry staining has demonstrated absence of the MSH6 protein in tumors of individuals with this mutation (Arnold A et al. Fam. Cancer. 2007 Feb;6:317-21; Kidambi TD et al. Fam. Cancer. 2017 Oct;16:537-543). This alteration was identified in a cohort of women undergoing multigene panel testing for hereditary cancer risk (Roberts ME et al. Genet Med. 2018 10;20:1167-1174). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, 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.
Invitae	RCV000630020	SCV000750976	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-08-19	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys545Argfs*25) in the MSH6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 17323113, 28283864, 28514183). ClinVar contains an entry for this variant (Variation ID: 89211). For these reasons, this variant has been classified as Pathogenic.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000761604	SCV000891769	pathogenic	Lynch syndrome 5	2018-08-24	criteria provided, single submitter	research	ACMG codes: PVS1, PM2, PP5
Myriad Genetics, Inc.	RCV000761604	SCV004188223	pathogenic	Lynch syndrome 5	2023-08-15	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	RCV003460664	SCV004198105	pathogenic	Endometrial carcinoma	2022-12-13	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000074674	SCV004829272	pathogenic	Lynch syndrome	2023-10-09	criteria provided, single submitter	clinical testing	This variant is predicted to result in loss of protein function through nonsense-mediated decay or protein truncation. Loss of function is an established mechanism of disease. This variant has been reported in multiple individuals with Lynch syndrome (PMID: 14974087, 18301448, 17323113, 28283864, 28514183, 36403965). This variant is absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/).
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000074674	SCV004848610	pathogenic	Lynch syndrome	2021-12-20	criteria provided, single submitter	clinical testing	The p.Lys545ArgfsX25 variant in MSH6 has been reported in an individual with Muir-Torre syndrome and their brother with colorectal cancer and in at least 2 individuals with clinical features of Lynch syndrome (Arnold 2007 PMID: 17323113, Susswein 2016 PMID: 26681312; PMID: 26681312, Kidambi 2017 PMID: 28283864, Espenschied 2017 PMID: 28514183). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 89211) and was absent from large population databases. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 545 and leads to a premature termination codon 25 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the MSH6 gene is an established disease mechanism in autosomal dominant Lynch syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PS4_Supporting.