rs63750439
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000179.3(MSH6):c.1190_1191del(p.Tyr397CysfsTer3) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000137 in 1,461,868 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. Y397Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000179.3 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MSH6 | NM_000179.3 | c.1190_1191del | p.Tyr397CysfsTer3 | frameshift_variant | 4/10 | ENST00000234420.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MSH6 | ENST00000234420.11 | c.1190_1191del | p.Tyr397CysfsTer3 | frameshift_variant | 4/10 | 1 | NM_000179.3 | P4 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251136Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135752
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461868Hom.: 0 AF XY: 0.00000138 AC XY: 1AN XY: 727238
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, no assertion criteria provided | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics and Genomics, Karolinska University Hospital | Feb 14, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 09, 2023 | 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) - |
Lynch syndrome 5 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Aug 11, 2023 | This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. - |
Pathogenic, criteria provided, single submitter | clinical testing | New York Genome Center | Jun 23, 2021 | 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. - |
Lynch syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 15, 2017 | 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. - |
Pathogenic, reviewed by expert panel | research | International Society for Gastrointestinal Hereditary Tumours (InSiGHT) | Sep 05, 2013 | Coding sequence variation resulting in a stop codon - |
Hereditary cancer-predisposing syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | curation | Sema4, Sema4 | May 08, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 06, 2022 | 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. - |
Gastric cancer Pathogenic:1
Pathogenic, no assertion criteria provided | research | Laboratory for Genotyping Development, RIKEN | Jul 01, 2021 | - - |
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 24, 2024 | 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. - |
Endometrial carcinoma Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 20, 2024 | - - |
Hereditary nonpolyposis colon cancer;C4552100:Lynch syndrome Other:1
not provided, no classification provided | phenotyping only | GenomeConnect - Invitae Patient Insights Network | - | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at