Submissions for variant NM_000179.3(MSH6):c.3939_3940dup (p.Gln1314fs)

dbSNP: rs730881830

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000497290	SCV000211389	pathogenic	not provided	2023-05-11	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); Observed in individuals with ovarian cancer and other individuals undergoing multi-gene panel testing whose cancer history was unclear (Susswein et al., 2016; Espenschied et al., 2017; Lilyquist et al., 2017; eMERGE Consortium 2019); This variant is associated with the following publications: (PMID: 26681312, 28152038, 28514183, 19851887, 14520694, 24440087, 28888541, 31447099)
Ambry Genetics	RCV000160746	SCV000273240	pathogenic	Hereditary cancer-predisposing syndrome	2022-04-16	criteria provided, single submitter	clinical testing	The c.3939_3940dupTC pathogenic mutation, located in coding exon 9 of the MSH6 gene, results from a duplication of TC at nucleotide position 3939, causing a translational frameshift with a predicted alternate stop codon (p.Q1314Lfs*14). This mutation has been identified in an individual who was diagnosed with bladder and colorectal cancer (Susswein LR et al. Genet. Med. 2016 Aug;18:823-32). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001260256	SCV000695900	pathogenic	Hereditary nonpolyposis colon cancer	2020-09-17	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.3939_3940dupTC (p.Gln1314LeufsX14) 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 was absent in 249986 control chromosomes. c.3939_3940dupTC has been reported in the literature in an individual affected with colorectal and bladder cancer (Susswein_2015) and in an individual screened for MMR mutations (phenotype not specified, Espenschied_2017). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000590196	SCV000711783	likely pathogenic	Lynch syndrome	2017-08-23	criteria provided, single submitter	clinical testing	The p.Gln1314fs variant in MSH6 has been reported in 1 individual with colorecta l and bladder cancer and 1 individual with unspecified cancer (Susswein 2015, Es penschied 2017). It has also been reported in ClinVar (Variation ID 182683) and was absent from large population studies, though the ability of these studies to accurately detect indels may be limited. This variant is predicted to cause a f rameshift, which alters the protein?s amino acid sequence beginning at position 1314 and leads to a premature termination codon 14 amino acids downstream. This termination codon occurs within the terminal 50 bases of the second to last exon and is more likely to escape nonsense mediated decay (NMD), resulting in a trun cated protein. Truncating variants downstream of this variant have been reported in individuals with Lynch syndrome. In summary, although additional studies ar e required to fully establish its clinical significance, the p.Gln1314fs variant is likely pathogenic.
Invitae	RCV000698894	SCV000827583	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-12-22	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln1314Leufs*14) in the MSH6 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 47 amino acid(s) of the MSH6 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with colorectal and bladder cancer (PMID: 26681312). ClinVar contains an entry for this variant (Variation ID: 182683). This variant disrupts a region of the MSH6 protein in which other variant(s) (p.Leu1330Valfs*12) have been determined to be pathogenic (PMID: 14520694, 19851887, 24440087). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc.	RCV003453274	SCV004188219	pathogenic	Lynch syndrome 5	2023-08-28	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	RCV003462100	SCV004196350	pathogenic	Endometrial carcinoma	2021-11-03	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000160746	SCV004357771	pathogenic	Hereditary cancer-predisposing syndrome	2022-11-03	criteria provided, single submitter	clinical testing	This variant inserts 2 nucleotides in exon 9 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 bladder and colorectal cancer (PMID: 26681312) and in an individual undergoing screening for mismatch repair gene mutations (PMID: 28514183). This variant has not been identified 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	RCV000590196	SCV004822743	pathogenic	Lynch syndrome	2022-11-22	criteria provided, single submitter	clinical testing	The c.3939_3940dupTC (p.Gln1314Leufs*14) variant in MSH6 gene creates a frameshift that results in a premature termination codon, predicted to cause truncated or absent of protein product due to nonsense mediated decay. This variant has been reported in an individual screened for mismatch repair mutations whose phenotype was not described (PMID: 28514183), in an individual with breast cancer (PMID: 29345684) and in an individual who was diagnosed with colorectal and bladder cancer (PMID: 26681312). Other frameshift variants affecting the same amino acid frame, c.3938_3941dupTTCA, c.3941_3942insTC has been reported to cause endometrial cancer, colorectal cancer and Lynch syndrome (PMID: 18269114, 26099011, 22658618, 30608896). Several truncating variants downstream of this variant region have been determined to be pathogenic and cause various cancer types (PMID:24440087, 19851887, 14520694). Truncating loss of function variants in MSH6 are known to be pathogenic (PMID: 14974087, 2815724, 18269114, 24362816). This variant was found to be absent in the general population according to gnomAD. Therefore, c.3939_3940dupTC (p.Gln1314Leufs*14) variant of MSH6 gene is classified as pathogenic.