MSH6 c.627+11G>A, p.?
NM_000179.3:c.627+11G>A
Variant of Uncertain Significance (VUS)
c.627+11G>A in MSH6 is intronic outside canonical splice sites, absent from population databases, with a possible splice impact prediction and a benign assertion in ClinVar. The combined moderate absence and supporting computational evidence is counterbalanced by a benign report, yielding a Variant of Uncertain Significance.
ACMG/AMP Criteria Applied
PM2
PP3
BP6
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.627+11G>A
Protein Change
?
Location
Exon 3
(Exon 3 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.627+11G>A
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
Likely Benign
Based on 1 submitter review in ClinVar
Submitter Breakdown
1 LB
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (0)
No publication details.
Clinical Statement
This variant has been reported in ClinVar as Likely benign (1 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
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 0.24
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to VCEP guidelines, PVS1 applies to variants at IVS±1 or IVS±2 where exon skipping disrupts the reading frame. The rule states: "Variants at IVS±1 or IVS±2 where exon skipping or use of a cryptic splice site disrupts reading frame and is predicted to undergo NMD." The evidence shows c.627+11G>A is at position +11, outside ±1/2. Therefore, PVS1 is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, PS1 applies to missense substitutions encoding the same amino acid as a known pathogenic variant. The rule states: "A predicted missense substitution that encodes the same amino acid change with a different underlying nucleotide change previously established as Pathogenic." The evidence shows c.627+11G>A is intronic with no amino acid change. Therefore, PS1 is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, PS2 requires de novo occurrences with parental confirmation. The rule states: "Very Strong ≥4 de novo points; Strong 2–3 de novo points; Moderate 1 de novo point; Supporting 0.5 de novo points." No de novo data are available for this variant. Therefore, PS2 is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines, PS3 requires calibrated functional assays demonstrating a damaging effect. The rule states: "Strong if functional odds >18.7; Moderate if >4.3 ≤18.7; Supporting if >2.08 ≤4.3." There are no functional studies for c.627+11G>A. Therefore, PS3 is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS4 requires statistical evidence of increased prevalence in affected individuals. There are no case–control or cohort data for c.627+11G>A. Therefore, PS4 is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, PM1 applies to variants in critical functional domains or mutational hotspots. The rule states: "Strong variants in initiation codon... or G>non-G at last base of exon..." There is no evidence that c.627+11G>A lies in a defined hotspot or functional domain. Therefore, PM1 is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, PM2_Supporting: "Absent/extremely rare (<1 in 50,000 alleles) in gnomAD v4 dataset." The evidence shows the variant is absent from gnomAD (MAF=0%). Therefore, PM2 is applied at Supporting strength.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, PM3 applies to in trans observations with a pathogenic variant in recessive disorders. The rule defines point-based strength for such observations. There are no co-occurrence data for this variant. Therefore, PM3 is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM4 applies to protein length changes such as in-frame insertions/deletions. c.627+11G>A is intronic with no predicted protein length effect. Therefore, PM4 is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM5 applies to novel missense changes at residues where different missense changes are pathogenic. This variant is intronic without an amino acid change. Therefore, PM5 is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to VCEP guidelines, PM6 is a de novo criterion without parental confirmation. There are no de novo data for c.627+11G>A. Therefore, PM6 is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, PP1 requires co-segregation with disease in families. There are no segregation data for this variant. Therefore, PP1 is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP2 applies to missense variants in genes intolerant to such changes. c.627+11G>A is intronic, not missense. Therefore, PP2 is not applied.
PP3
PP3 (Supporting)
According to VCEP guidelines, PP3_Supporting: "Predicted splice defect for non-canonical splicing nucleotides using SpliceAI with delta score ≥0.2." The evidence shows SpliceAI predicts a donor loss score of 0.38. Therefore, PP3 is applied at Supporting strength.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines, PP4 requires tumor phenotype data (MSI-H or loss of MMR protein) consistent with Lynch syndrome. No such phenotype data are available. Therefore, PP4 is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP5 applies to pathogenic assertions from reputable sources without available evidence. ClinVar asserts Likely Benign, not Pathogenic. Therefore, PP5 is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, BA1 applies for allele frequency ≥0.22% in gnomAD v4. The variant is absent (0%). Therefore, BA1 is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, BS1 applies for allele frequency between 0.022% and 0.22%. The variant is absent (0%). Therefore, BS1 is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, BS2 requires co-occurrence in trans with a pathogenic variant in a healthy adult. No such data are available. Therefore, BS2 is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, BS3 requires calibrated functional assays demonstrating no damaging effect. No functional assays exist. Therefore, BS3 is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, BS4 requires lack of co-segregation with disease. No segregation data are available. Therefore, BS4 is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP1 applies to missense variants in genes where only truncating variants cause disease. c.627+11G>A is intronic. Therefore, BP1 is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP2 applies to observed in trans with a pathogenic variant in unaffected individuals. No such observations exist. Therefore, BP2 is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP3 applies to in-frame indels in repetitive regions. c.627+11G>A is a single-nucleotide intronic variant with no evidence of repetitive region. Therefore, BP3 is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, BP4_Supporting: "SpliceAI predicts no splicing impact with delta score ≤0.1 for intronic variants." The evidence shows a SpliceAI score of 0.38 (>0.1). Therefore, BP4 is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines, BP5 requires tumors with inconsistent MMR protein expression or MSS. No tumor data are available. Therefore, BP5 is not applied.
BP6
BP6 (Supporting)
According to standard ACMG guidelines, BP6_Supporting: "Reputable source recently reports variant as benign but evidence is not available." ClinVar lists this variant as Likely Benign by one laboratory. Therefore, BP6 is applied at Supporting strength.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP7 applies to synonymous or intronic variants at or beyond –21/+7 with no predicted splicing impact. Although c.627+11G>A is intronic beyond +7, SpliceAI predicts potential splicing impact (0.38). Therefore, BP7 is not applied.