2-47799427-C-T
Variant summary
Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000179.3(MSH6):c.1444C>T(p.Arg482*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000558 in 1,613,850 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. R482R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000179.3 stop_gained
Scores
Clinical Significance
Conservation
Publications
- intellectual developmental disorder with dysmorphic facies and behavioral abnormalitiesInheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
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ACMG classification
Our verdict: Pathogenic. The variant received 16 ACMG points.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_000179.3. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| MSH6 | NM_000179.3 | MANE Select | c.1444C>T | p.Arg482* | stop_gained | Exon 4 of 10 | NP_000170.1 | ||
| MSH6 | NM_001406795.1 | c.1540C>T | p.Arg514* | stop_gained | Exon 5 of 11 | NP_001393724.1 | |||
| MSH6 | NM_001406813.1 | c.1450C>T | p.Arg484* | stop_gained | Exon 4 of 10 | NP_001393742.1 |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| MSH6 | ENST00000234420.11 | TSL:1 MANE Select | c.1444C>T | p.Arg482* | stop_gained | Exon 4 of 10 | ENSP00000234420.5 | ||
| MSH6 | ENST00000445503.5 | TSL:1 | n.*791C>T | non_coding_transcript_exon | Exon 3 of 9 | ENSP00000405294.1 | |||
| MSH6 | ENST00000445503.5 | TSL:1 | n.*791C>T | 3_prime_UTR | Exon 3 of 9 | ENSP00000405294.1 |
Frequencies
GnomAD3 genomes 0.00000658 AC: 1AN: 151978Hom.: 0 Cov.: 32 show subpopulations
GnomAD4 exome AF: 0.00000547 AC: 8AN: 1461872Hom.: 0 Cov.: 34 AF XY: 0.00000550 AC XY: 4AN XY: 727234 show subpopulations
Age Distribution
GnomAD4 genome 0.00000658 AC: 1AN: 151978Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74230 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
not provided Pathogenic:5
MSH6: PVS1, PP1, PS3:Supporting
Nonsense 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; Not observed at significant frequency in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Observed in multiple individuals with Lynch syndrome-associated cancers, including colon cancers which demonstrate absence of MSH6 protein by immunohistochemistry (Hendriks 2004, Nilbert 2009, Baglietto 2010, Sjursen 2010, Klarskov 2011, Okkels 2012, Therkildsen 2015, Yurgelun 2015, Young 2018); This variant is associated with the following publications: (PMID: 28460341, 15236168, 20587412, 18566915, 25648859, 25980754, 22495361, 25525159, 20028993, 19575290, 18415027, 26517685, 27013479, 21836479, 29945567, 32710294, 31297992, 30291343, 32832836, 32794656)
Lynch syndrome 5 Pathogenic:4
This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.
Criteria applied: PVS1,PS4_MOD,PM2_SUP
Lynch syndrome Pathogenic:4
Coding sequence variation resulting in a stop codon
The c.1444C>T variant in the MSH6 gene is located on the exon 4 and introduces a premature translation termination codon (p.Arg482*), resulting in an absent or disrupted protein product. The variant has been reported in multiple individuals with Lynch syndrome-associated cancer (PMID: 22495361, 26517685, 27601186, 20587412, 26437257). Loss-of-function variants of MSH6 are known to be pathogenic (PMID: 30376427, 18269114, 29345684). Other loss-of-function variants located in the same exon (p.Tyr433*, p.Tyr524*) have been interpreted as pathogenic by the expert panel (ClinVar ID: 89185, 89202). This variant has been reported as pathogenic by the expert review panel in ClinVar (ID: 89194). This variant is rare (9/1613850 chromosomes) in general population according to gnomAD. Therefore, the c.1444C>T (p.Arg482*) variant in the MSH6 gene has been classified as pathogenic.
PVS1; PM2_SUP; PP4_SUP
Endometrial carcinoma Pathogenic:3
ACMG classification criteria: PVS1 very strong, PS4 strong, PM2 moderated
Hereditary cancer-predisposing syndrome Pathogenic:2
The p.R482* pathogenic mutation (also known as c.1444C>T), located in coding exon 4 of the MSH6 gene, results from a C to T substitution at nucleotide position 1444. This changes the amino acid from an arginine to a stop codon within coding exon 4. This mutation was detected in a family that met Amsterdam II criteria and the mutation showed moderate segregation with disease (Hendriks YM et al. Gastroenterology 2004 Jul;127(1):17-25). The mutation has also been reported in multiple patients with hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome, some of whom have been shown to have tumors with loss of MSH6 protein on immunohistochemistry (IHC) (Nilbert M et al. Fam. Cancer 2009 Jun;8(1):75-83; Jensen UB et al. Breast Cancer Res. Treat. 2010 Apr;120:777-82; Okkels H et al. Appl. Immunohistochem. Mol. Morphol. 2012 Oct;20:470-7). The p.R482* mutation was identified in a 34 year-old woman with choroid plexus carcinoma (CPC) that demonstrated absence of MSH6 protein by IHC (Zhu VW et al. Clin Neurol Neurosurg 2017 Jul;158:46-48). 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.
This variant changes 1 nucleotide in exon 4 of the MSH6 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with Lynch syndrome (PMID: 15236168, 19575290, 20587412, 22495361, 28460341) and colorectal cancer (PMID: 20028993). This variant has been identified in 1/31384 chromosomes 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.
Carcinoma of colon Pathogenic:1
The MSH6 p.Arg482X variant was identified in 6 of 3135 proband chromosomes (frequency: 0.002) from individuals or families with CRC and prostate cancer (Hendriks 2004, Nilbert 2008, Dominguez-Valentin 2016). The variant was also identified in dbSNP (ID: rs63750909) as “With Pathogenic allele” ,ClinVar (5x, as pathogenic, by InSight, Invitae, GeneDx, Counsyl, Ambry Genetics), Clinvitae (3x, as pathogenic, by ClinVar and Clinvitae), Cosmic (as pathogenic), UMD-LSDB (8 records, as causal), Insight Colon Cancer Gene Variant Database (4x, as class 5, pathogenic), Mismatch Repair Genes Variant Database (2x as pathogenic), Insight Hereditary Tumors Database (5x , as class 5, "affects function”). The variant was not identified in MutDB, GeneInsight-COGR, Zhejiang Colon Cancer databases. The variant was identified in control databases in 1 of 30956 chromosomes at a frequency of 0.000032 in East Asian population (Genome Aggregation Consortium Feb 27, 2017). The p.Arg482X variant leads to a premature stop codon at position 482, which is predicted to lead to a truncated or absent protein and loss of function.4. Loss of function variants of the MSH6 gene are an established mechanism of disease in colorectal cancer 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.
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
This sequence change creates a premature translational stop signal (p.Arg482*) 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 (rs63750909, gnomAD 0.06%). This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 15236168, 20028993, 20587412, 21836479, 22495361). 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: 89194). For these reasons, this variant has been classified as Pathogenic.
Hereditary breast ovarian cancer syndrome Pathogenic:1
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at