The MSH6 NM_000179.3:c.3334G>A (p.Asp1112Asn, p.D1112N) variant has been reported in ClinVar with predominantly uncertain significance submissions and a smaller number of likely benign submissions.1 This variant is present in population databases, including gnomAD v4.1 at 76/1613996 alleles (AF 0.00004709; grpmax FAF 0.00004535) and gnomAD v2.1 at 8/282750 alleles (AF 0.00002829), and is absent from gnomAD-Canada; the gnomAD v4.1 frequency is above the MSH6 PM2 threshold of <0.00002 but below the BS1 threshold of 0.00022.2 For MSH6 missense prediction, the HCI prior probability is 0.5901, which is below the PP3 thresholds of >0.68 and >0.81 and above the BP4 threshold of <0.11; REVEL is 0.71, BayesDel is -0.0786, and SpliceAI predicts no significant splice effect with a maximum delta score of 0.04.3
MSH6
Final classification
VUS
MSH6 c.3334G>A · p.Asp1112Asn
MSH6
The MSH6 NM_000179.3:c.3334G>A (p.Asp1112Asn, p.D1112N) variant has been reported in ClinVar with predominantly uncertain significance submissions and a smaller number of likely benign 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 was evaluated deterministically with applied criteria: none; no rule matched the adjudicated criteria.
Classification rationale
VUS
MSH6 c.3334G>A
3
hci_priorrevelbayesdelspliceai ↗cspec ↗
Gene diagram
· NM_000179.3 · variants mapped to exon structure
MSH6
NM_000179.3
Fetching transcript structure from UCSC…
Applied criteria · 0 applied · 16 assessed
Applied · 0
No criteria were applied for this variant.
Assessed · not applied
Pathogenic
PS1
No previously established pathogenic or likely pathogenic alternate nucleotide change producing the same amino acid substitution was identified, so PS1 cannot be applied from the available evidence.
PS2
No confirmed de novo data were identified, so PS2 cannot be assessed.
PS3
No variant-specific calibrated functional evidence showing an MMR defect or marked allelic expression loss was identified, so PS3 cannot be applied.
PM2
This variant is present in gnomAD v4.1 at 76/1613996 alleles (AF 0.00004709), which is above the MSH6 PM2 threshold of <0.00002, so PM2 is not met.
PM3
No qualifying observations in trans with another pathogenic MSH6 variant in the constitutional mismatch repair deficiency framework were identified, so PM3 cannot be assessed.
PM5
No verified same-residue pathogenic or likely pathogenic missense comparator at codon 1112 was identified from the available comparator materials, so PM5 cannot be applied from the current evidence.
PP1
No segregation data were identified, so PP1 cannot be applied.
PP3
For MSH6 missense variants, PP3 uses the HCI prior.
PP4
No tumor microsatellite instability or mismatch repair immunohistochemistry results were identified to support the MSH6-specific PP4 tumor phenotype thresholds.
Benign
BA1
The gnomAD v4.1 filtering allele frequency for this variant is 0.00004535, which is below the MSH6 BA1 threshold of 0.0022, so BA1 is not met.
BS1
The gnomAD v4.1 filtering allele frequency for this variant is 0.00004535, which is below the MSH6 BS1 threshold of 0.00022, so BS1 is not met.
BS2
No confirmed in trans co-occurrence with a known pathogenic MSH6 variant in an individual meeting the VCEP age and CMMRD exclusions was identified, so BS2 cannot be assessed.
BS3
No variant-specific calibrated functional evidence showing proficient MMR function or normal RNA effect was identified, so BS3 cannot be applied.
BS4
No non-segregation data were identified, so BS4 cannot be applied.
BP4
For MSH6 missense variants, BP4 uses the HCI prior.
BP5
No tumor findings showing MSS, retained MMR protein expression, or inconsistent MMR loss patterns were identified, so BP5 cannot be assessed.
N/A · 12
PVS1 · PS4 · PM1 · PM4 · PM6 · PP2 · PP5 · BP1 · BP2 · BP3 · BP6 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 4.70881e-05; MAF= 0.00471%, 76/1613996 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000128025; MAF= 0.01280%, 8/62488 alleles, homozygotes = 0); grpmax FAF= 4.535e-05.
v2.1
This variant is present in gnomAD v2.1 (AF= 2.82935e-05; MAF= 0.00283%, 8/282750 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 6.1978e-05; MAF= 0.00620%, 8/129078 alleles, homozygotes = 0); grpmax FAF= 2.855e-05.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.0047%
· 76 / 1,613,996
0 hom · FAF 0.0045%
0 hom · FAF 0.0045%
Remaining individuals 8 / 62,488 |
0.013% |
European (non-Finnish) 67 / 1,180,032 |
0.0057% |
African/African American 1 / 74,902 |
0.0013% |
+ 7 not observed (Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish)
gnomAD v2.1
0.0028%
· 8 / 282,750
0 hom · FAF 0.0029%
0 hom · FAF 0.0029%
European (non-Finnish) 8 / 129,078 |
0.0062% |
+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (14 clinical laboratories) and as Likely benign (2 clinical laboratories) and as Uncertain Significance (1 clinical laboratory). (ClinVarID = 220784)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04). REVEL score = 0.71. BayesDel score = -0.0786165. HCI prior probability for pathogenicity = 0.5901. MAPP score = 13.97. Custom PP2 score = 0.84.
Functional
Unknown Oncogenic Effect
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. MSH6, a DNA mismatch repair protein, is frequently mutated in colorectal, small bowel, and endometrial cancers.
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
9Sources
Triaged references · 11 PMIDs not cited in assessment
24033266 ↗
A systematic approach to assessing the clinical significance of genetic variants.
CLINVAR
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
26467025 ↗
A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.
CLINVAR
26689913 ↗
Patterns and functional implications of rare germline variants across 12 cancer types.
CLINVAR
17392385 ↗
American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography.
CLINVAR
20065170 ↗
American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility.
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR