Submissions for variant NM_000179.3(MSH6):c.1815_1816del (p.Lys606fs)

dbSNP: rs1060502886

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000470844	SCV000551078	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-12-05	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys606Asnfs*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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with colorectal cancer (PMID: 26485756). Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this MSH6 variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 1,370,736 individuals referred to our laboratory for MSH6 testing. ClinVar contains an entry for this variant (Variation ID: 410412). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000486089	SCV000569502	pathogenic	not provided	2016-06-29	criteria provided, single submitter	clinical testing	This deletion of two nucleotides in MSH6 is denoted c.1815_1816delTA at the cDNA level and p.Lys606AsnfsX33 (K606NfsX33) at the protein level. The normal sequence, with the bases that are deleted in braces, is AAAC[TA]AAAC. The deletion causes a frameshift which changes a Lysine to an Asparagine at codon 606, and creates a premature stop codon at position 33 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. MSH6 c.1815_1816delTA, also denoted MSH6 c.1815delTA using alternative nomenclature, has been observed at least once, in an individual with colorectal cancer who met Bethesda Guidelines (Maccaroni 2015). We consider this variant to be pathogenic.
Ambry Genetics	RCV000491721	SCV000580086	pathogenic	Hereditary cancer-predisposing syndrome	2023-03-14	criteria provided, single submitter	clinical testing	The c.1815_1816delTA pathogenic mutation, located in coding exon 4 of the MSH6 gene, results from a deletion of two nucleotides at nucleotide positions 1815 to 1816, causing a translational frameshift with a predicted alternate stop codon (p.K606Nfs*33). This mutation was identified in an HNPCC family from Latvia (Irmejs A et al. Hered Cancer Clin Pract. 2003;1(1):49–53). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Color Diagnostics, LLC DBA Color Health	RCV000491721	SCV001352054	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	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 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001199932	SCV001370717	pathogenic	Hereditary nonpolyposis colon cancer	2022-12-12	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.1815_1816delTA (p.Lys606AsnfsX33) 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 250498 control chromosomes (gnomAD). c.1815_1816delTA has been reported in the literature in individuals affected with Hereditary Nonpolyposis Colorectal Cancer (HNPCC) associated tumors, including one proband who was also noted to meet the Amsterdam II criteria for late onset HNPCC (e.g. Irmejs_2003, Maccaroni_2015, Waszak_2018, Dong_2020). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Myriad Genetics, Inc.	RCV003449142	SCV004188305	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	RCV003463927	SCV004196381	pathogenic	Endometrial carcinoma	2021-03-05	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000486089	SCV005413392	pathogenic	not provided	2023-11-07	criteria provided, single submitter	clinical testing	PP4, PM2_moderate, PVS1
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV005055442	SCV005689662	likely pathogenic	Lynch syndrome	2025-02-04	criteria provided, single submitter	clinical testing	PVS1; PM2_SUP;
PreventionGenetics, part of Exact Sciences	RCV004533196	SCV004709854	pathogenic	MSH6-related disorder	2023-10-27	no assertion criteria provided	clinical testing	The MSH6 c.1815_1816delTA variant is predicted to result in a frameshift and premature protein termination (p.Lys606Asnfs*33). This variant was reported in an individual with colorectal cancer (described as c.1815delTA T605fsX638 in Table 2 in Maccaroni et al 2015. PubMed ID: 26485756) and in an individual with medulloblastoma (Supplementary Table 2 in Waszak SM et al 2018. PubMed ID: 29753700). In ClinVar, this variant is interpreted as pathogenic by multiple clinical laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/410412/). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Frameshift variants in MSH6 are expected to be pathogenic. This variant is interpreted as pathogenic.