rs63750647
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PM4_SupportingPP5_Very_Strong
The NM_000179.3(MSH6):βc.2302_2304delβ(p.Pro768del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ). Synonymous variant affecting the same amino acid position (i.e. T767T) has been classified as Likely benign.
Frequency
Consequence
NM_000179.3 inframe_deletion
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MSH6 | NM_000179.3 | c.2302_2304del | p.Pro768del | inframe_deletion | 4/10 | ENST00000234420.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MSH6 | ENST00000234420.11 | c.2302_2304del | p.Pro768del | inframe_deletion | 4/10 | 1 | NM_000179.3 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461880Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 727238
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 21, 2021 | In-frame deletion of 1 amino acid in a non-repeat region; Observed in patients with Lynch-related cancers and tumor studies consistent with pathogenic variants in this gene (Lagerstedt-Robinson 2007, Nilbert 2009, Sjursen 2010, DeRycke 2017); Not observed in large population cohorts (Lek 2016); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20587412, 28944238, 18566915, 24689082, 17312306) - |
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Apr 09, 2023 | Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. ClinVar contains an entry for this variant (Variation ID: 89266). This variant is also known as c.2303delCCT. This variant has been observed in individuals with Lynch syndrome or clinical features of Lynch syndrome (PMID: 17312306, 20587412, 27601186, 28944238; externalcommunication). This variant is not present in population databases (gnomAD no frequency). This variant, c.2302_2304del, results in the deletion of 1 amino acid(s) of the MSH6 protein (p.Pro768del), but otherwise preserves the integrity of the reading frame. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 05, 2020 | The c.2302_2304delCCT pathogenic mutation (also known as p.P768del) is located in coding exon 4 of the MSH6 gene. This variant results from an in-frame CCT deletion between nucleotide positions 2302 and 2304. The proline at codon 768 is deleted. This mutation has been reported in multiple families who met either Bethesda guidelines or Amsterdam criteria, with several individuals with concordant tumor immunohistochemistry (IHC) data showing loss of MSH6 expression (Sjursen W et al. J. Med. Genet. 2010 Sep; 47(9):579-85; Lagerstedt Robinson K et al. J. Natl. Cancer Inst. 2007 Feb; 99(4):291-9). This mutation has also been shown to co-segregate with disease in several affected individuals from two unrelated families (personal communication, Ambry internal data). This amino acid position is located in an allosteric region and is required to allow flexibility in the region (Warren JJ et al. Mol. Cell 2007 May; 26(4):579-92). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE 2012;7(10):e46688). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at