Submissions for variant NM_000179.3(MSH6):c.1190_1191del (p.Tyr397fs)

dbSNP: rs63750439

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000074640	SCV000107842	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
GeneDx	RCV000497288	SCV000211379	pathogenic	not provided	2023-06-09	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; 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 early-onset colon cancer who had tumors showing microsatellite instability and/or loss of MSH6 on immunohistochemistry staining (Plaschke et al., 2004; Steinke et al., 2008; You et al., 2010; Yang et al., 2021); This variant is associated with the following publications: (PMID: 14974087, 32980694, 29922827, 18301448, 21081928, 26681312, 15483016, 36988593, 34178123)
Ambry Genetics	RCV000160740	SCV000580232	pathogenic	Hereditary cancer-predisposing syndrome	2022-06-06	criteria provided, single submitter	clinical testing	The c.1190_1191delAT pathogenic mutation, located in coding exon 4 of the MSH6 gene, results from a deletion of two nucleotides at nucleotide positions 1190 to 1191, causing a translational frameshift with a predicted alternate stop codon (p.Y397Cfs*3). This mutation was previously reported in an individual with a sigmoid colon tumor at age 33 that was noted to be MSI-H and have absent MSH6 expression by IHC analysis (Plaschke J et al. Hum. Mutat. 2004 Mar;23:285). 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	RCV000074640	SCV000919727	pathogenic	Lynch syndrome	2017-11-15	criteria provided, single submitter	clinical testing	Variant summary: The MSH6 c.1190_1191delAT (p.Tyr397CysfsX3) 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. One in silico tool predicts a damaging outcome for this variant. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.1444C>T (p.Arg482X), c.1572C>A (p.Tyr524X), c.1634_1637delAAGA (p.Lys545fsX25)). The variant has been observed in patients with HNPCC-associated cancers (i.e. CRC and cancer of the endometrium), in one of them a CRC tumor sample showing loss of MSH6 and microsatellite instability (Plaschke 2004, Susswein 2015). This variant was found in 2/245974 control chromosomes at a frequency of 0.0000081, which does not exceed the estimated maximal expected allele frequency of a pathogenic MSH6 variant (0.0001421). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae	RCV001045033	SCV001208862	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr397Cysfs*3) 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 (rs756896277, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 14974087, 15483016, 26681312). ClinVar contains an entry for this variant (Variation ID: 89178). For these reasons, this variant has been classified as Pathogenic.
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000497288	SCV001449662	pathogenic	not provided	2017-02-14	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000160740	SCV002535610	pathogenic	Hereditary cancer-predisposing syndrome	2021-05-08	criteria provided, single submitter	curation
New York Genome Center	RCV002265594	SCV002548624	pathogenic	Lynch syndrome 5	2021-06-23	criteria provided, single submitter	clinical testing	The inherited c.1190_1191del (p.Tyr397CysfsTer3) variant identified in the MSH6 gene is the deletion of two nucleotides resulting in a frameshift of the protein at amino acid 397/1361 (exon 4/10), which is predicted to lead to the termination of the protein approximately 3 amino acids downstream. This variant is absent from gnomAD(v3.1.1) suggesting it is not a common benign variant in the populations represented in that database. This variant has been reviewedby an Expert Panel and reported in ClinVar as Pathogenic (VarID:89178) and has been reported in several affected individuals in the literature [PMID:15483016,18301448, 21081928]. The inherited c.1190_1191del (p.Tyr397CysfsTer3) variant identified in the MSH6 gene is reported as Pathogenic.
Myriad Genetics, Inc.	RCV002265594	SCV004188307	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.
Baylor Genetics	RCV003460659	SCV004198125	pathogenic	Endometrial carcinoma	2022-10-13	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000497288	SCV000691923	pathogenic	not provided		no assertion criteria provided	clinical testing
GenomeConnect - Invitae Patient Insights Network	RCV001535637	SCV001749666	not provided	Lynch syndrome; Hereditary nonpolyposis colon cancer		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 07-12-2017 by Myriad. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
Laboratory for Genotyping Development, RIKEN	RCV003162469	SCV002758358	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research