MSH6 c.3859delinsATTA, p.Tyr1287delinsIleAsn
NM_000179.3:c.3859delinsATTA
Variant of Uncertain Significance (VUS)
The variant c.3859delinsATTA (Y1287delinsIN) in MSH6 is classified as VUS. Evidence includes PM4 (Moderate) for in‐frame protein length change, PM2 and PP5 (Supporting) for absence in controls and a ClinVar report, counterbalanced by BP4 (Supporting) for lack of predicted splicing impact. No strong or very strong criteria apply, and conflicting benign and pathogenic supporting evidence precludes definitive classification.
ACMG/AMP Criteria Applied
PM2
PM4
PP5
BP4
Genetic Information
Gene & Transcript Details
Gene
MSH6
Transcript
NM_000179.3
MANE Select
Total Exons
10
Strand
Forward (+)
Reference Sequence
NC_000002.11
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_000179.2 | RefSeq Select | 10 exons | Forward |
| NM_000179.1 | Alternative | 10 exons | Forward |
Variant Details
HGVS Notation
NM_000179.3:c.3859delinsATTA
Protein Change
Y1287delinsIN
Location
Exon 9
(Exon 9 of 10)
5'Exon Structure (10 total)3'
Functional Consequence
Loss of Function
Related Variants
Variant interpretation based on transcript NM_000179.3
Genome Browser
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HGVS InputNM_000179:c.3859delinsATTA
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.05%
0.1%
1%
5%
10%+
ACMG Criteria Applied
PM2
This variant is not present in gnomAD (PM2 criteria applies).
Classification
1 publications
Likely Pathogenic
Based on 3 submitter reviews in ClinVar
Submitter Breakdown
1 LP
2 VUS
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (1)
The 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.
Clinical Statement
This variant has been reported in ClinVar as Likely pathogenic (1 clinical laboratories) and as Uncertain significance (2 clinical laboratories).
Functional Impact
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Unknown
PP3 Applied
No
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
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
PS1 (Not Applied) Strength Modified
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
PS2 (Not Applied) Strength Modified
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
PS3 (Not Applied) Strength Modified
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
PS4 (Not Applied) Strength Modified
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
PM1 (Not Applied) Strength Modified
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
PM2 (Supporting) Strength Modified
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
PM3 (Not Applied) Strength Modified
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
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
PM5 (Not Applied) Strength Modified
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
PM6 (Not Applied) Strength Modified
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
PP1 (Not Applied) Strength Modified
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
PP2 (Not Applied) Strength Modified
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
PP3 (Not Applied) Strength Modified
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
PP4 (Not Applied) Strength Modified
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
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
BA1 (Not Applied) Strength Modified
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
BS1 (Not Applied) Strength Modified
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
BS2 (Not Applied) Strength Modified
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
BS3 (Not Applied) Strength Modified
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
BS4 (Not Applied) Strength Modified
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
BP1 (Not Applied) Strength Modified
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
BP2 (Not Applied) Strength Modified
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
BP3 (Not Applied) Strength Modified
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
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
BP5 (Not Applied) Strength Modified
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
BP6 (Not Applied) Strength Modified
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
BP7 (Not Applied) Strength Modified
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.