2-47800714-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.2731C>T(p.Arg911*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,613,924 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. R911R) 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.2731C>T | p.Arg911* | stop_gained | Exon 4 of 10 | NP_000170.1 | ||
| MSH6 | NM_001406795.1 | c.2827C>T | p.Arg943* | stop_gained | Exon 5 of 11 | NP_001393724.1 | |||
| MSH6 | NM_001406813.1 | c.2737C>T | p.Arg913* | 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.2731C>T | p.Arg911* | stop_gained | Exon 4 of 10 | ENSP00000234420.5 | ||
| MSH6 | ENST00000445503.5 | TSL:1 | n.*2078C>T | non_coding_transcript_exon | Exon 3 of 9 | ENSP00000405294.1 | |||
| MSH6 | ENST00000445503.5 | TSL:1 | n.*2078C>T | 3_prime_UTR | Exon 3 of 9 | ENSP00000405294.1 |
Frequencies
GnomAD3 genomes 0.0000132 AC: 2AN: 152082Hom.: 0 Cov.: 32 show subpopulations
GnomAD4 exome AF: 0.0000137 AC: 20AN: 1461842Hom.: 0 Cov.: 34 AF XY: 0.0000193 AC XY: 14AN XY: 727228 show subpopulations
Age Distribution
GnomAD4 genome 0.0000132 AC: 2AN: 152082Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74274 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
not provided Pathogenic:8
MSH6: PVS1, PM2, PS4:Moderate
The MSH6 c.2731C>T; p.Arg911Ter variant (rs63751017) has previously been described in individuals and families with Lynch syndrome (Goodfellow 2003, Pal 2012, Plaschke 2004, Rosty 2014, Talseth-Palmer 2010). It is reported in the ClinVar database as pathogenic (Variation ID: 89312), and observed in the general population at a very low allele frequency of 0.008 percent (1/13006 alleles) in the Exome Variant Server, and 0.003 percent (1/30970 alleles) in the Genome Aggregation Database. This variant induces an early termination codon and is predicted to result in a truncated protein or absent transcript. Based on the above information, this variant is considered pathogenic. REFERENCES Link to ClinVar database for p.Arg911Ter: https://www.ncbi.nlm.nih.gov/clinvar/variation/89312/ Goodfellow PJ et al. Prevalence of defective DNA mismatch repair and MSH6 mutation in an unselected series of endometrial cancers. Proc Natl Acad Sci U S A. 2003 May 13;100(10):5908-13. Pal T et al. Frequency of mutations in mismatch repair genes in a population-based study of women with ovarian cancer. Br J Cancer. 2012 Nov 6;107(10):1783-90. Plaschke J et al. Lower incidence of colorectal cancer and later age of disease onset in 27 families with pathogenic MSH6 germline mutations compared with families with MLH1 or MSH2 mutations: the German Hereditary Nonpolyposis Colorectal Cancer Consortium. J Clin Oncol. 2004 Nov 15;22(22):4486-94. Rosty C et al. High prevalence of mismatch repair deficiency in prostate cancers diagnosed in mismatch repair gene mutation carriers from the colon cancer family registry. Fam Cancer. 2014 Dec;13(4):573-82. Talseth-Palmer BA et al. MSH6 and PMS2 mutation positive Australian Lynch syndrome families: novel mutations, cancer risk and age of diagnosis of colorectal cancer. Hered Cancer Clin Pract. 2010 May 21;8(1):5.
This nonsense variant is predicted to cause the premature termination of MSH6 protein synthesis. In the published literature, the variant has been reported in multiple individuals suspected of having Lynch syndrome in the published literature (PMIDs: 15236168 (2004), 23263490 (2013), 25117503 (2014), 26681312 (2015), 28176205 (2017), 29212164 (2017), 29978187 (2018), 30521064 (2019), 31857677 (2020), 32242007 (2020)). Based on the available information, this variant is classified as likely pathogenic.
PP4, PM2, PS4_moderate, PVS1
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; 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); This variant is associated with the following publications: (PMID: 24244552, 25117503, 29978187, 25525159, 23263490, 12732731, 15483016, 25637381, 15098177, 20487569, 23047549, 28176205, 26681312, 28873162, 20028993, 25559809, 16885385, 29212164, 15236168, 29760388, 29750335, 30521064, 31857677, 32242007, 31447099, 32081490, 31589614, 32719484, 30787465, 33087929, 34178123, 29130549)
Lynch syndrome 5 Pathogenic:5
The c.2731C>T (p.Arg911*) variant in the MSH6 gene is predicted to introduce a premature translation stop codon. This variant has been reported in the literature in multiple individuals with ovarian, colorectal, or prostate cancer (PMID: 12732731, 23047549, 23263490, 15236168, 15483016, 25117503, 16885385). The c.2731C>T (p.Arg911*) variant in the MSH6 gene is classified as pathogenic.
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.
Lynch syndrome Pathogenic:5
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. To our knowledge, functional studies have not been reported for this variant. This variant has been observed in individuals affected with colorectal, ovarian, endometrial, small bowel and prostate cancer (PMID: 12732731, 15483016, 16885385, 19723918, 20587412, 25117503, 25559809, 26681312, 28176205, 29212164, 32081490, 32941469), in families affected with Lynch syndrome (PMID: 15236168, 20028993, 20487569, 23263490), and an individual affected with uveal melanoma (PMID: 32081490). This variant has been identified in 1/31398 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.
The p.Arg911X variant in MSH6 has been reported in at least 13 individual with MSH6-associated cancers and segregated in at least 4 affected relatives (Goodfellow 2003, Buttin 2004, Hendriks 2004, Plaschke 2004, Hampel 2006, Talseth-Palmer 2010, Pal 2012, Palles 2013, Rosty 2014, Susswein 2015, Akbari 2017, Raskin 2017). This variant has also been reported in ClinVar (Variation ID 89312) and has been identified in 1/15426 European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This nonsense variant leads to a premature termination codon at position 911, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the MSH6 gene is an established disease mechanism in individuals with Lynch syndrome. In summary, this variant meets criteria to be classified as pathogenic for Lynch syndrome in an autosomal dominant manner. ACMG/AMP Criteria applied: PVS1; PS4; PP1; PM2.
This variant results in a single amino acid substitution, replacing Arginine with a premature stop codon at position 911 of the MSH6 protein (p.Arg911*). This change is predicted to lead to a truncated or absent protein product. Truncating (loss-of-function) variants in MSH6 are a known cause of disease and are classified as pathogenic (PMID:18269114, 24362816). This specific premature stop codon has been reported in individuals diagnosed with Lynch syndrome (PMID:12732731, 15483016, 20487569, 23047549, 23263490). The variant is also listed in the ClinVar database with Variation ID:89312. For these reasons, the variant is classified as pathogenic.
Coding sequence variation resulting in a stop codon
PVS1; PM2_SUP; PP4
Hereditary cancer-predisposing syndrome Pathogenic:4
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. To our knowledge, functional studies have not been reported for this variant. This variant has been observed in individuals affected with colorectal, ovarian, endometrial, small bowel and prostate cancer (PMID: 12732731, 15483016, 16885385, 19723918, 20587412, 25117503, 25559809, 26681312, 28176205, 29212164, 32081490, 32941469), in families affected with Lynch syndrome (PMID: 15236168, 20028993, 20487569, 23263490), and an individual affected with uveal melanoma (PMID: 32081490). This variant has been identified in 1/31398 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.
PVS1, PM2_Supporting, PP4_Strong c.2731C>T, located in exon 4 of the MSH6 gene, is expected to result in loss of function by premature protein truncation before codon 911, p.(Arg911*)(PVS1)This variant is found in 1/267843 at a frequency of 0.0004% in the gnomAD v2.1.1 database, non-cancer data set (PM2_Supporting). No effect is predicted on splicing by computational tools. It has been identified in several patients affected with colorectal and/or endometrial cancer with tumors showing loss of MSH6 protein expression (internal data) (PP4_Strong).In addition, it was identified in the databases: InSiGHT (Class 5 pathogenic: Class 5: Coding sequence variation resulting in a stop codon), in the ClinVar database (26x pathogenic) and in the LOVD (18x pathogenic, 1x likely pathogenic, 1x not provided) databases. Based on currently available information, the variant c.2731C>T is classified as a pathogenic variant according to ACMG guidelines.
The p.R911* pathogenic mutation (also known as c.2731C>T), located in coding exon 4 of the MSH6 gene, results from a C to T substitution at nucleotide position 2731. This changes the amino acid from an arginine to a stop codon within coding exon 4. This mutation has been reported in multiple individuals and families diagnosed with hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome (Goodfellow PJ et al. Proc. Natl. Acad. Sci. USA. 2003 May;100:5908-13; Hendriks YM et al. Gastroenterology. 2004 Jul;127:17-25; Plaschke J et al. J. Clin. Oncol. 2004 Nov;22:4486-94; Hampel H et al. Cancer Res. 2006 Aug;66:7810-7; Baglietto L et al. J. Natl. Cancer Inst. 2010 Feb;102:193-201; Palles C et al. Nat. Genet. 2013 Feb;45:136-44; Chubb D et al. J. Clin. Oncol. 2015 Feb;33:426-32; Susswein LR et al. Genet. Med. 2016 Aug;18:823-32; Raskin L et al. Oncotarget. 2017 Nov;8:93450-93463). 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.
Endometrial carcinoma Pathogenic:2
Endometrial carcinoma;C1833477:Lynch syndrome 5;C5436807:Mismatch repair cancer syndrome 3 Pathogenic:1
Carcinoma of colon Pathogenic:1
The MSH6 p.Arg311* variant has been previously reported in the literature in at least 5 of 2738 proband chromosomes in individuals with Lynch syndrome related tumours and microsatellite instability (Selected publications: Plaschke 2004, Hendriks 2004, Hampel 2006, Goodfellow 2003). The p.Arg311* variant is predicted to cause a premature stop codon at position 311, which is then predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the MSH6 gene are an established mechanism for Lynch syndrome and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant is classified as pathogenic.
Hereditary nonpolyposis colon cancer Pathogenic:1
Variant summary: MSH6 c.2731C>T (p.Arg911X) 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 250878 control chromosomes. c.2731C>T has been reported in the literature in multiple individuals affected with Hereditary Nonpolyposis Colorectal Cancer and endometrial cancer (e.g. Goodfellow_2003, Hendricks_2004, Plasche_2004, Hampel_2006, Talseth-Palmer_2010). These data indicate that the variant is very likely to be associated with disease. Thirteen ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Gastric cancer Pathogenic:1
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
This sequence change creates a premature translational stop signal (p.Arg911*) 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 (rs63751017, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 12732731, 15483016, 20487569, 23047549, 23263490). 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: 89312). For these reasons, this variant has been classified as Pathogenic.
Breast carcinoma Pathogenic:1
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at