The MSH6 NM_000179.3:c.3483T>C (NP_000170.1:p.(Pro1161=)) variant has been reported in ClinVar predominantly as likely benign or benign, with 4 likely benign and 1 benign clinical laboratory submissions.1 This variant is rare in population databases, with gnomAD v4.1 overall AF 1.86e-06 (3/1,614,056 alleles) and highest observed subpopulation AF 3.20e-05 (2/62,482 alleles), which is below the MSH6 BS1 threshold of 0.00022 and BA1 threshold of 0.0022 but within the PM2_Supporting rarity threshold of <0.00002.2 This is a synonymous change, NP_000170.1:p.(Pro1161=), located 44 nucleotides from the exon 6 acceptor and 73 nucleotides from the donor, and SpliceAI predicts no splice effect (max delta score 0.00), supporting BP7 and BP4 rather than PP3.3
Final classification
Likely Benign
PM2BP7BP4
MSH6
c.3483T>C
p.Pro1161=
This variant
The MSH6 NM_000179.3:c.3483T>C (NP_000170.1:p.(Pro1161=)) variant has been reported in ClinVar predominantly as likely benign or benign, with 4 likely benign and 1 benign clinical laboratory submissions.
ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MSH6 Version 2.0.0 v2.0.0 criteria-combination framework: matched Rule19 (Benign.Supporting >=2) with applied criteria: BP7 supporting, PM2 supporting, BP4 supporting; maps to Likely Benign.
Classification rationale
PM2
BP7BP4
Likely Benign
MSH6 c.3483T>C
PM2 + BP7 + BP4
→
Likely Benign
LYFE Sciences is an AI system, and it can make mistakes. Criteria
may be applied incorrectly, sources may be misread, and a confident-looking
classification can still be wrong. Double-check every criterion and
its underlying evidence before relying on any call.
Gene diagram
· NM_000179.3 · variants mapped to exon structure
MSH6
NM_000179.3
Fetching transcript structure from UCSC…
Applied criteria · 3 applied · 13 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 3
Strength
Supporting
Moderate
Strong
Very strong
PM2
supporting
Pathogenic
This variant is extremely rare in population databases. In gnomAD v4.1, the overall allele frequency is 1.86e-06 (3/1,614,056 alleles), which is below the MSH6 PM2_Supporting threshold of 0.00002.
gnomAD v4.1 overall AF 1.85867e-06 (3/1614056)MSH6 PM2 threshold <0.00002
BP4
supporting
Benign
Computational splice prediction supports a benign interpretation. For this synonymous variant, SpliceAI shows a maximum delta score of 0.00, which is below the MSH6 BP4 threshold of 0.1 for no predicted splicing impact.
SpliceAI max delta score 0.00MSH6 BP4 threshold <=0.1 for synonymous/intronic variants
BP7
supporting
Benign
This is a synonymous MSH6 variant, NM_000179.3:c.3483T>C (NP_000170.1:p.(Pro1161=)), located well away from the splice junctions in exon 6 (44 nucleotides from the acceptor and 73 nucleotides from the donor), which satisfies the BP7 location requirement for a silent exonic change beyond -21/+7.
Synonymous protein consequence p.(Pro1161=)Exon 6 position is beyond the BP7 splice-region exclusion zone
Assessed · not applied
· 4 not met · 9 not assessed
Pathogenic
PVS1
PVS1 is not met.
PS2
No confirmed de novo data were identified, so PS2 cannot be assessed.
PS3
No calibrated pathogenic functional assay or variant-specific RNA evidence demonstrating an abnormal effect was identified, so PS3 cannot be assessed.
PM3
No qualifying recessive phase data or point-based in trans observations were identified, so PM3 cannot be assessed.
PP1
No segregation data were identified, so PP1 cannot be assessed.
PP3
Computational evidence does not support PP3.
PP4
No tumor microsatellite instability or mismatch repair immunohistochemistry evidence was identified, so PP4 cannot be assessed.
Benign
BA1
Population data do not meet BA1.
BS1
Population data do not meet BS1.
BS2
No phase-confirmed in trans observation with a known pathogenic MSH6 variant in an older patient without clinical features of CMMRD was identified, so BS2 cannot be assessed from the available evidence.
BS3
No RNA study with nonsense-mediated decay inhibition or other qualifying calibrated benign functional assay was identified for this variant, so BS3 cannot be assessed.
BS4
No non-segregation data were identified, so BS4 cannot be assessed.
BP5
No tumor data showing mismatch repair findings inconsistent with MSH6-related disease were identified, so BP5 cannot be assessed.
N/A · 12
PS1 · PS4 · PM1 · PM4 · PM5 · PM6 · PP2 · PP5 · BP1 · BP2 · BP3 · BP6
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 1.85867e-06; MAF= 0.00019%, 3/1614056 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 3.20092e-05; MAF= 0.00320%, 2/62482 alleles, homozygotes = 0).
v2.1
This variant is present in gnomAD v2.1 (AF= 7.95551e-06; MAF= 0.00080%, 2/251398 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000108743; MAF= 0.01087%, 2/18392 alleles, homozygotes = 0); grpmax FAF= 1.897e-05.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00019%
· 3 / 1,614,056
0 hom
0 hom
Remaining individuals 2 / 62,482 |
0.0032% |
East Asian 1 / 44,900 |
0.0022% |
+ 8 not observed (Admixed American, European (Finnish), Amish, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish))
gnomAD v2.1
0.0008%
· 2 / 251,398
0 hom · FAF 0.0019%
0 hom · FAF 0.0019%
East Asian 2 / 18,392 |
0.011% |
+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, European (Finnish), European (non-Finnish), Remaining individuals, South Asian)
ClinVar
This variant has been reported in ClinVar as Likely benign (4 clinical laboratories) and as Benign (1 clinical laboratory). (ClinVarID = 380626)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
Functional
Unknown Oncogenic Effect
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
Triaged references · 9 PMIDs not cited in assessment
25741868 ↗
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
CLINVAR
23788249 ↗
ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing.
CLINVAR
25356965 ↗
ACMG policy statement: updated recommendations regarding analysis and reporting of secondary findings in clinical genome-scale sequencing.
CLINVAR
25394175 ↗
A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.
CLINVAR
27854360 ↗
Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics.
CLINVAR
34012068 ↗
ACMG SF v3.0 list for reporting of secondary findings in clinical exome and genome sequencing: a policy statement of the American College of Medical Genetics and Genomics (ACMG).
CLINVAR
34043773 ↗
European guidelines from the EHTG and ESCP for Lynch syndrome: an updated third edition of the Mallorca guidelines based on gene and gender.
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR