Submissions for variant NM_000179.3(MSH6):c.2504del (p.Gln835fs)

gnomAD frequency: 0.00001  dbSNP: rs1572727440

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000804861	SCV000944797	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-10-27	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln835Argfs*9) 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 clinical features of Lynch syndrome (PMID: 20028993, 30608896, 30877237). ClinVar contains an entry for this variant (Variation ID: 649835). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV001015780	SCV001176654	pathogenic	Hereditary cancer-predisposing syndrome	2023-09-20	criteria provided, single submitter	clinical testing	The c.2504delA pathogenic mutation, located in coding exon 4 of the MSH6 gene, results from a deletion of one nucleotide at nucleotide position 2504, causing a translational frameshift with a predicted alternate stop codon (p.Q835Rfs*9). This mutation was identified in an individual with a personal history of colorectal cancer at age 42 and endometrial cancer at age 45, and functional analysis for this alteration demonstrated reduced mismatch repair activity (Shuen AY et al. J. Clin. Oncol., 2019 02;37:461-470). This mutation has also been reported as a germline mutation in a Canadian individual (Baglietto L et al. J. Natl. Cancer Inst., 2010 Feb;102:193-201). 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.
Revvity Omics, Revvity	RCV003141805	SCV003820167	pathogenic	not provided	2022-11-29	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003453679	SCV004188284	pathogenic	Lynch syndrome 5	2023-08-17	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	RCV003467407	SCV004198123	pathogenic	Endometrial carcinoma	2022-10-17	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354871	SCV001549587	likely pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	The MSH6 p.Gln835Argfs*9 variant was identified in 1 of 838 proband chromosomes (frequency: 0.001) from individuals or families with colorectal cancer (Hampel 2018). The variant was also identified in Insight Hereditary Tumors Database (1x). The variant was not identified in dbSNP, ClinVar, Clinvitae, COGR, Cosmic, MutDB, UMD-LSDB, Zhejiang University Database, or Mismatch Repair Genes Variant Database. The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.2504del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 835 and leads to a premature stop codon at position 843. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the MSH6 gene are an established mechanism of disease in Lynch syndrome and is the type of variant expected to cause the disorder. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic.