Submissions for variant NM_000179.3(MSH6):c.1610_1613del (p.Lys537fs)

dbSNP: rs863224829

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000791395	SCV000255259	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-03-23	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 216859). This premature translational stop signal has been observed in individual(s) with colorectal and pancreatic cancer (PMID: 28514183, 28975465, 29360161). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Lys537Ilefs*33) 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).
Ambry Genetics	RCV000213843	SCV000277173	pathogenic	Hereditary cancer-predisposing syndrome	2019-04-26	criteria provided, single submitter	clinical testing	The c.1610_1613delAGTA pathogenic mutation, located in coding exon 4 of the MSH6 gene, results from a deletion of 4 nucleotides at nucleotide positions 1610 to 1613, causing a translational frameshift with a predicted alternate stop codon (p.K537Ifs*33). This mutation was identified in a Saudi individual with colorectal cancer (Siraj AK et al. Hum. Genet. 2017 11;136:1431-1444) and in a woman with both pancreatic and rectal cancer (Dudley B et al. Cancer 2018 Apr;124:1691-1700). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000196707	SCV000695789	likely pathogenic	Lynch syndrome	2017-01-31	criteria provided, single submitter	clinical testing	Variant summary: The MSH6 c.1610_1613delAGTA (p.Lys537Ilefs) variant results in a premature termination codon, predicted to cause a truncated or absent MSH6 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.1634_1637delAAGA, c.1637_1638delAG). One in silico tool predicts a damaging outcome for this variant. This variant was found in 1/121328 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic MSH6 variant (0.0001421). The variant was reported in a conference abstract (European Human Genetics Conference 2014) in a patient with multiple primary tumors between 21 and 27 years of age including two metachronous colorectal cancers, a fillodes tumour of the breast, a glioblastoma and a clear cell carcinoma of the ovaries who also carried MSH6 p.Arg1076His (not classified by LabCorp, VUS in ClinVar). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as likely pathogenic.
GeneDx	RCV000657535	SCV000779271	pathogenic	not provided	2021-12-08	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 a significant frequency in large population cohorts (Lek et al., 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Observed in patients with Lynch-related cancers and tumor studies consistent with pathogenic variants in this gene (Siraj et al. 2017, Dudley et al. 2018); This variant is associated with the following publications: (PMID: 31350202, 28975465, 29360161, 28152038, 29625052, 30787465)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000657535	SCV000888244	pathogenic	not provided	2018-04-24	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003454504	SCV004185678	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	RCV003468911	SCV004196362	pathogenic	Endometrial carcinoma	2021-08-14	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000196707	SCV004839573	pathogenic	Lynch syndrome	2023-07-19	criteria provided, single submitter	clinical testing	This variant deletes 4 nucleotides in exon 4 of the MSH6 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with Lynch syndrome (PMID: 33647816), or Lynch syndrome-associated cancers (PMID: 28975465, 29360161). This variant has been identified in 1/251346 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH6 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.