rs587779937
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM4_SupportingPP3
The NM_000179.3(MSH6):c.3762_3764del(p.Glu1254del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,614,156 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. V1253V) 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 Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MSH6 | NM_000179.3 | c.3762_3764del | p.Glu1254del | inframe_deletion | 8/10 | ENST00000234420.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MSH6 | ENST00000234420.11 | c.3762_3764del | p.Glu1254del | inframe_deletion | 8/10 | 1 | NM_000179.3 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152224Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251190Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135760
GnomAD4 exome AF: 0.0000116 AC: 17AN: 1461814Hom.: 0 AF XY: 0.0000110 AC XY: 8AN XY: 727206
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152342Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74502
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 08, 2022 | The c.3762_3764delAGA variant (also known as p.E1254del) is located in coding exon 8 of the MSH6 gene. This variant results from an in-frame AGA deletion at nucleotide positions 3762 to 3764. This results in the in-frame deletion of a glutamic acid at codon 1254. This alteration was identified in a cohort of 1260 individuals undergoing panel testing for Lynch syndrome due to having a diagnosis of a Lynch-associated cancer and/or polyps. (Yurgelun MB et al. Gastroenterology, 2015 Sep;149:604-13.e20). 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). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 23, 2022 | This variant deletes three nucleotides in exon resulting in an in-frame deletion of a glutamine in MSH6 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual suspected of having Lynch syndrome (PMID: 25980754). This variant has been identified in 7/282588 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 20, 2023 | Variant summary: MSH6 c.3762_3764delAGA (p.Glu1254del) results in an in-frame deletion that is predicted to remove one amino acid from the DNA mismatch repair protein MutS, C-terminal domian (IPR000432) of the encoded protein. The variant allele was found at a frequency of 2.4e-05 in 251190 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3762_3764delAGA has been reported in the literature as a VUS in settings of multigene panel testing in one individual with a history of LS-associated cancer and/or colorectal polyps (Yurgelun_2015).. These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer/Lynch syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 25980754). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 21, 2018 | This in-frame deletion of three nucleotides in MSH6 is denoted c.3762_3764delAGA at the cDNA level and p.Glu1254del (E1254del) at the protein level. The normal sequence, with the bases that are deleted in brackets, is TAGA[delAGA]TTAT. MSH6 Glu1254del, also defined as 3762del3 using alternate nomenclature, was observed in one individual who underwent clinical genetic testing for Lynch Syndrome (Yurgelun 2015). This variant was not observed at a significant allele frequency in large population cohorts (Lek 2016). This deletion of a single Glutamic Acid amino acid is located in the ATPase domain (Warren 2007, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. Since in-frame deletions may or may not inhibit proper protein functioning, the clinical significance of this finding remains unclear at this time and we consider MSH6 Glu1254del to be a variant of uncertain significance. - |
Hereditary nonpolyposis colorectal neoplasms Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 29, 2023 | This variant, c.3762_3764del, results in the deletion of 1 amino acid(s) of the MSH6 protein (p.Glu1254del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs757589867, gnomAD 0.02%). This variant has been observed in individual(s) with breast cancer or clinical features of Lynch syndrome (PMID: 25980754, 35449176). ClinVar contains an entry for this variant (Variation ID: 127592). 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 available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Endometrial carcinoma Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 31, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at