Submissions for variant NM_000179.3(MSH6):c.1108_1109del (p.Leu370fs)

dbSNP: rs786204252

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000168455	SCV000219152	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-01-17	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu370Argfs*4) 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 present in population databases (rs786204252, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with clinical features of MSH6-related conditions (PMID: 26687385). ClinVar contains an entry for this variant (Variation ID: 188393). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000491275	SCV000580308	pathogenic	Hereditary cancer-predisposing syndrome	2023-03-09	criteria provided, single submitter	clinical testing	The c.1108_1109delTT pathogenic mutation, located in coding exon 4 of the MSH6 gene, results from a deletion of two nucleotides at nucleotide positions 1108 to 1109, causing a translational frameshift with a predicted alternate stop codon (p.L370Rfs*4). 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	RCV001255565	SCV001432046	likely pathogenic	Hereditary nonpolyposis colon cancer	2020-08-05	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.1108_1109delTT (p.Leu370ArgfsX4) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the 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. The variant allele was found at a frequency of 4e-06 in 250994 control chromosomes (gnomAD). To our knowledge, no occurrence of c.1108_1109delTT in individuals affected with Hereditary Nonpolyposis Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Myriad Genetics, Inc.	RCV003454425	SCV004187416	pathogenic	Lynch syndrome 5	2023-08-11	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Color Diagnostics, LLC DBA Color Health	RCV000491275	SCV004357571	pathogenic	Hereditary cancer-predisposing syndrome	2023-06-20	criteria provided, single submitter	clinical testing	This variant deletes 2 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 an individual affected with early onset endometrial cancer from a family affected with Lynch syndrome-associated disease (PMID: 26687385). This variant has been identified in 1/250994 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.
All of Us Research Program, National Institutes of Health	RCV003995628	SCV004842947	pathogenic	Lynch syndrome	2023-05-03	criteria provided, single submitter	clinical testing	The c.1108_1109del (p.Leu370Argfs*4) variant of the MSH6 gene is located on the exon 4 and is predicted to cause reading frame shift that introduces a premature translation termination codon (p.Leu370Argfs*4), resulting in an absent or disrupted protein product. The variant has been reported in 3 individuals with endometrial cancer and 1 individual with colon cancer in a family (PMID: 26687385). Loss-of-function variants located downstream to this position have been reported in individuals with Lynch syndrome-associated cancer (PMID: 20028993). The variant is reported in ClinVar (ID: 188393). The variant is rare in the general population according to gnomAD (1/250994). Therefore, the c.1108_1109del (p.Leu370Argfs*4) variant of MSH6 has been classified as pathogenic.