Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_000179.3 | MANE Select | 4265 nt | 90–4172 |
| NM_000179.2 | RefSeq Select | 4435 nt | 153–4235 |
| NM_000179.1 | Alternative | 4264 nt | 88–4170 |
Variant Details
Clinical & Population Data
Population Frequency
gnomADClinVar
OpenThe c.3859delTinsATTA variant (also known as p.Y1287delinsIN), located in coding exon 9 of the MSH6 gene, results from an in-frame deletion of T and insertion of ATTA at nucleotide position 3859. This results in the deletion of a tyrosine residue at codon 1287 and insertion of an isoleucine and asparagine residue. This variant has been identified in probands whose Lynch syndrome-associated tumor demonstrated loss of MSH6 expression by immunohistochemistry (Li S et al. J. Med. Genet. 2020 Jan;57:62-69; Ambry internal data). Based on internal structural analysis, Y1287delinsIN is predicted to disrupt an important interaction with ATP in the MutS domain V (Mao L et al. J Mol Biol, 2004 Feb;336:787-807; Warren JJ et al. Mol Cell, 2007 May;26:579-92; Ambry internal data). 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 majority of available evidence to date, this variant is likely to be pathogenic.
"This variant has been reported in ClinVar as Likely pathogenic (1 clinical laboratories) and as Uncertain significance (2 clinical laboratories)."
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.01 | 49 bp |
| Donor Loss (DL) | 0.02 | 142 bp |
| Acceptor Gain (AG) | 0.0 | -301 bp |
| Donor Gain (DG) | 0.0 | 394 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to VCEP guidelines, the rule for PVS1 is: "Very Strong Nonsense/frameshift variant introducing Premature Termination Codon (PTC) ≤ codon 1341 in MSH6...". The evidence for this variant shows: it is an in‐frame delins (Y1287delinsIN), not a nonsense or frameshift variant introducing a PTC. Therefore, this criterion is not applied.
PS1 (Not Applied)
According to standard ACMG guidelines, the rule for PS1 is: "Strong: Same amino acid change as a previously established pathogenic variant regardless of nucleotide change." The evidence for this variant shows: it is a delins, not a missense encoding a previously established pathogenic amino acid change. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to standard ACMG guidelines, the rule for PS2 is: "Strong: De novo (both maternity and paternity confirmed) in a patient with the disease and no family history." The evidence for this variant shows: no de novo data have been reported. Therefore, this criterion is not applied.
PS3 (Not Applied)
According to standard ACMG guidelines, the rule for PS3 is: "Strong: Well‐established functional studies supportive of a damaging effect on the gene or gene product." The evidence for this variant shows: no functional studies have been conducted. Therefore, this criterion is not applied.
PS4 (Not Applied)
According to standard ACMG guidelines, the rule for PS4 is: "Strong: The prevalence of the variant in affected individuals is significantly increased compared with controls." The evidence for this variant shows: no case‐control or segregation data. Therefore, this criterion is not applied.
PM1 (Not Applied)
According to standard ACMG guidelines, the rule for PM1 is: "Moderate: Located in a mutational hot spot and/or critical and well‐established functional domain without benign variation." The evidence for this variant shows: no data indicating location in a hot spot or critical domain. Therefore, this criterion is not applied.
PM2 (Supporting)
According to VCEP guidelines, the rule for PM2 is: "Supporting: Absent/extremely rare (<1 in 50,000 alleles) in gnomAD v4 dataset." The evidence for this variant shows: it is not found in gnomAD or other population databases (MAF=0%). Therefore, this criterion is applied at Supporting strength.
PM3 (Not Applied)
According to standard ACMG guidelines, the rule for PM3 is: "Moderate: Detected in trans with a pathogenic variant for a recessive disorder." The evidence for this variant shows: MSH6‐related Lynch syndrome is autosomal dominant and no trans observations reported. Therefore, this criterion is not applied.
PM4 (Moderate)
According to standard ACMG guidelines, the rule for PM4 is: "Moderate: Protein length changes due to in‐frame deletions/insertions in a non‐repeat region." The evidence for this variant shows: an in‐frame delins resulting in Y1287delinsIN. Therefore, this criterion is applied at Moderate strength.
PM5 (Not Applied)
According to standard ACMG guidelines, the rule for PM5 is: "Moderate: Novel missense change at an amino acid residue where a different missense change is pathogenic." The evidence for this variant shows: it is an indel, not a novel missense. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to standard ACMG guidelines, the rule for PM6 is: "Supporting: Assumed de novo, but without confirmation of paternity and maternity." The evidence for this variant shows: no de novo or parental data. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to standard ACMG guidelines, the rule for PP1 is: "Supporting: Co‐segregation with disease in multiple affected family members." The evidence for this variant shows: no segregation data available. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, the rule for PP2 is: "Supporting: Missense variant in a gene with low rate of benign missense variation." The evidence for this variant shows: it is an indel, not a missense. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to standard ACMG guidelines, the rule for PP3 is: "Supporting: Multiple lines of computational evidence support a deleterious effect." The evidence for this variant shows: SpliceAI delta score 0.02 (no impact) and no strong deleterious predictions. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to VCEP guidelines, the rule for PP4 is: "Supporting: Tumor data consistent with gene function (e.g., MSI‐H and protein loss)." The evidence for this variant shows: no tumor or MSI data. Therefore, this criterion is not applied.
PP5 (Supporting)
According to standard ACMG guidelines, the rule for PP5 is: "Supporting: Reputable source reports variant as pathogenic without evidence available." The evidence for this variant shows: ClinVar lists one submission as Likely Pathogenic with no accessible evidence. Therefore, this criterion is applied at Supporting strength.
BA1 (Not Applied)
According to VCEP guidelines, the rule for BA1 is: "Stand Alone: GnomAD v4 filtering allele frequency ≥0.22%." The evidence for this variant shows: absent from population databases. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines, the rule for BS1 is: "Strong: GnomAD v4 filtering allele frequency between 0.022–0.22%." The evidence for this variant shows: absent from population databases. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to VCEP guidelines, the rule for BS2 is: "Strong: Co‐occurrence in trans with a known pathogenic variant in healthy adults for LS genes." The evidence for this variant shows: no such co‐occurrence data. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to standard ACMG guidelines, the rule for BS3 is: "Strong: Well‐established functional studies show no damaging effect." The evidence for this variant shows: no functional assays performed. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to standard ACMG guidelines, the rule for BS4 is: "Strong: Lack of segregation in families." The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
BP1 (Not Applied)
According to standard ACMG guidelines, the rule for BP1 is: "Supporting: Missense variant in gene where only truncating variants cause disease." The evidence for this variant shows: it is an indel, not a missense. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to standard ACMG guidelines, the rule for BP2 is: "Supporting: Observed in trans with a pathogenic variant for a dominant disorder." The evidence for this variant shows: no such observations. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: "Supporting: In‐frame indel in a repetitive region without known function." The evidence for this variant shows: region context unknown. Therefore, this criterion is not applied.
BP4 (Supporting)
According to VCEP guidelines, the rule for BP4 is: "Supporting: For intronic and synonymous variants, SpliceAI predicts no splicing impact with delta score ≤0.1." The evidence for this variant shows: SpliceAI maximum delta score of 0.02. Therefore, this criterion is applied at Supporting strength.
BP5 (Not Applied)
According to standard ACMG guidelines, the rule for BP5 is: "Supporting: Variant found in a case with an alternate molecular basis for disease." The evidence for this variant shows: no alternate molecular basis reported. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, the rule for BP6 is: "Supporting: Reputable source reports variant as benign without evidence." The evidence for this variant shows: no such reports. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to standard ACMG guidelines, the rule for BP7 is: "Supporting: Synonymous variant with no predicted splice impact." The evidence for this variant shows: it is an indel, not synonymous. Therefore, this criterion is not applied.