Submissions for variant NM_000179.3(MSH6):c.2677_2678del (p.Leu893fs)

dbSNP: rs1572728112

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001016284	SCV001177223	pathogenic	Hereditary cancer-predisposing syndrome	2024-04-04	criteria provided, single submitter	clinical testing	The c.2677_2678delCT pathogenic mutation, located in coding exon 4 of the MSH6 gene, results from a deletion of two nucleotides at nucleotide positions 2677 to 2678, causing a translational frameshift with a predicted alternate stop codon (p.L893Afs*6). This mutation has been identified in a patient with endometrial cancer whose tumor was microsatellite stable with intact immunohistochemical (IHC) staining (Rubio I et al. Oncology, 2016 Jul;91:171-6), and in a patient with colorectal cancer whose tumor was microsatellite-low with absent MSH6 staining by IHC, who had a family history of Lynch syndrome-related cancers (Vilar E et al. Cancer Genet Oct;207:495-502). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001058469	SCV001223043	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-03-07	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu893Alafs*6) 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 variant has not been reported in the literature in individuals affected with MSH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 821660). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV001016284	SCV001352055	pathogenic	Hereditary cancer-predisposing syndrome	2020-02-10	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. To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. 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.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV001354264	SCV004026237	likely pathogenic	not provided	2023-01-25	criteria provided, single submitter	clinical testing	PVS1, PM2_SUP
Myriad Genetics, Inc.	RCV003455092	SCV004188215	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.
CeGaT Center for Human Genetics Tuebingen	RCV001354264	SCV005432701	pathogenic	not provided	2024-11-01	criteria provided, single submitter	clinical testing	MSH6: PVS1, PM2, PS4:Supporting
Constitutional Genetics Lab, Leon Berard Cancer Center	RCV001249987	SCV001424001	pathogenic	Lynch-like syndrome	2019-07-01	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354264	SCV001548836	pathogenic	not provided		no assertion criteria provided	clinical testing	The MSH6 p.Leu893Alafs*6 variant was identified in 1 of 142 proband chromosomes (frequency: 0.007) from an individual with Lynch syndrome and a family history of ovarian, breast, and prostate cancer (Vilar 2014). The variant was also identified in UMD-LSDB (1x as causal). The variant was not identified in dbSNP, ClinVar, the Exome Aggregation Consortium (August 8th 2016) or the Genome Aggregation Database (Feb 27, 2017). The c.2677_2678del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 893 and leads to a premature stop codon at position 898. 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, this variant meets our laboratory’s criteria to be classified as pathogenic.
CZECANCA consortium	RCV003128163	SCV003804327	pathogenic	Endometrial carcinoma	2023-02-21	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004726783	SCV005337678	pathogenic	MSH6-related disorder	2024-08-15	no assertion criteria provided	clinical testing	The MSH6 c.2677_2678delCT variant is predicted to result in a frameshift and premature protein termination (p.Leu893Alafs*6). This variant was reported in individuals with breast, endometrial, and colorectal cancer (Supplementary Table 4. Hata et al. 2020. PubMed ID: 32029870; Table 3. Rubio et al. 2016. PubMed ID: 27398995; Table 4. Vilar et al. 2014. PubMed ID: 25432668). This variant has not been reported in a large population database, indicating this variant is rare. This variant has classifications listed in ClinVar ranging from likely pathogenic to pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/821660/). Frameshift variants in MSH6 are expected to be pathogenic. This variant is interpreted as pathogenic.