rs63750194
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000179.3(MSH6):c.3513_3514delTA(p.Asp1171GlufsTer5) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★★). 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
Ensembl
Frequencies
GnomAD3 genomes
GnomAD4 genome
ClinVar
Submissions by phenotype
not provided Pathogenic:3
This deletion of two nucleotides in MSH6 is denoted c.3513_3514delTA at the cDNA level and p.Asp1171GlufsX5 (D1171EfsX5) at the protein level. The normal sequence, with the bases that are deleted in braces, is TTGA[TA]GAGT. The deletion causes a frameshift, which changes an Aspartic Acid to a Glutamic Acid at codon 1171, and creates a premature stop codon at position 5 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.3513_3514delTA has been reported in individuals with colorectal and endometrial cancer, with most tumors demonstrating abnormal mismatch repair protein expression, and is classified as pathogenic by the International Society for Gastrointestinal Hereditary Tumors Incorporated (Steinke 2008, Buchanan 2014, Thompson 2014, Kraus 2015). We consider this variant to be pathogenic. -
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Hereditary cancer-predisposing syndrome Pathogenic:3
This variant deletes 2 nucleotides in exon 6 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. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with Lynch syndrome (PMID: 29107668, 18301448, 14974087) and in individuals with endometrial or colorectal cancers (PMID: 25142776, 24323032). 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. -
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The c.3513_3514delTA pathogenic mutation, located in coding exon 6 of the MSH6 gene, results from a deletion of two nucleotides between positions 3513 and 3514, causing a translational frameshift with a predicted alternate stop codon (p.D1171Efs*5). This alteration was previously reported in a man with ascending colon cancer at 31 years whose tumor demonstrated high microsatellite instability and isolated absence of MSH6 on immunohistochemistry (IHC) (Plaschke J et al. Hum Mutat. 2004 Mar;23(3):285). This alteration was also reported in a woman diagnosed with serous endometrial cancer at 51 years whose tumor demonstrated isolated absence of MSH6 on IHC (Buchanan DD et al. J. Clin. Oncol. 2014 Jan;32(2):90-100). This alteration has been reported in a man diagnosed with colon cancer at age 56 years whose tumor demonstrated microsatellite stability and normal protein expression on IHC (Kraus C et al. Int. J. Cancer. 2015 Mar 15;136(6):E559-68). Additionally, this alteration has been detected in a Polish patient with prostate cancer (Wokoorczyk D et al. Int J Cancer. 2020 11;147:2793-2800). 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. -
Lynch syndrome 5 Pathogenic:2
This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
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Lynch syndrome Pathogenic:2
Coding sequence variation resulting in a stop codon -
The p.Asp1171fs variant in MSH6 has been reported in 3 individuals with Lynch sy ndrome associated cancers (Plaschke 2004, Buchanan 2014 Steinke 2008). This vari ant was absent from large population studies, though the ability of these studie s to accurately detect indels may be limited. This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at posit ion 1171 and leads to a premature termination codon 5 amino acids downstream. Th is alteration is then predicted to lead to a truncated or absent protein. Heter ozygous loss of function of the MSH6 gene is an established disease mechanism in individuals with Lynch syndrome. In addition, this variant was classified as p athogenic on Sep 5, 2013 by the ClinGen-approved InSiGHT expert panel (ClinVar S CV000108082.2). In summary, this variant meets criteria to be classified as path ogenic for Lynch syndrome in an autosomal dominant manner based upon the predict ed impact to the protein and absence from controls. -
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
This sequence change creates a premature translational stop signal (p.Asp1171Glufs*5) 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 variant has not been reported in the literature in individuals affected with MSH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 89403). For these reasons, this variant has been classified as Pathogenic. -
Endometrial carcinoma Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at