Classification rationale

PM2 VUS

MSH6 c.-2G>T

The MSH6 NM_000179.3:c.-2G>T (NP_000170.1:p.?) variant has not been observed in COSMIC and has been reported in ClinVar with mixed single-submitter interpretations, including uncertain significance and likely benign.¹ This variant is present at very low frequency in population databases, with gnomAD v4.1 total allele frequency 1.24133e-05 (20/1611176 alleles) and gnomAD v2.1 total allele frequency 1.45244e-05 (4/275398 alleles), which supports PM2_Supporting under the MSH6 VCEP threshold of less than 0.00002.² Available evidence does not show a qualifying constitutional RNA or other calibrated functional study for this variant, so PS3 and BS3 are not currently supported.³ SpliceAI predicts no significant splice impact for this variant with a max delta score of 0.00, but this 5′ UTR substitution does not fit the MSH6 VCEP PP3 or BP4 rule types for missense or qualifying intronic/non-canonical splice variants.⁴

PM2 → VUS

1 clinvar ↗

2 gnomad_v4 ↗gnomad_v2 ↗cspec ↗

3 cspec ↗PMID:26888055 ↗vcep_functional_assay_svi_documentation_mmrvcep_functional_assay_flowchart

4 spliceai ↗cspec ↗

Gene diagram · NM_000179.3 · variants mapped to exon structure

MSH6 NM_000179.3

Fetching transcript structure from UCSC…

Applied criteria · 1 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

PS

PM

PP

Benign evidence

BA

BS

BP

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 1.24133e-05; MAF= 0.00124%, 20/1611176 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.0002404; MAF= 0.02404%, 15/62396 alleles, homozygotes = 0); grpmax FAF= 2.987e-05.

v2.1

This variant is present in gnomAD v2.1 (AF= 1.45244e-05; MAF= 0.00145%, 4/275398 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000141084; MAF= 0.01411%, 1/7088 alleles, homozygotes = 0).

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.0012% · 20 / 1,611,176
0 hom · FAF 0.003%

Remaining individuals 15 / 62,396	0.024%
East Asian 4 / 44,672	0.009%
European (non-Finnish) 1 / 1,179,344	8.5e-05%

+ 7 not observed (Admixed American, European (Finnish), Amish, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)

gnomAD v2.1

0.0015% · 4 / 275,398
0 hom

Remaining individuals 1 / 7,088	0.014%
East Asian 2 / 19,398	0.01%
South Asian 1 / 30,236	0.0033%

+ 5 not observed (African/African American, Admixed American, Ashkenazi Jewish, European (Finnish), European (non-Finnish))

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Uncertain significance (8 clinical laboratories) and as Likely benign (5 clinical laboratories). (ClinVarID = 142219)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

SpliceAI ↗

Functional No data

No calibrated functional assay or RNA evidence was identified for this variant.

OncoKB ↗

COSMIC

Somatic evidence

COSMIC

This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant cancer hotspot.

COSMIC ↗

Sources & reference links

7Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Triaged references · 9 PMIDs not cited in assessment

25070057 ↗ Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the US Multi-society Task Force on colorectal cancer. CLINVAR

25645574 ↗ ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes. 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

26888055 ↗ Understanding the Pathogenicity of Noncoding Mismatch Repair Gene Promoter Variants in Lynch Syndrome. CLINVAR

28301460 ↗ Clinical laboratories collaborate to resolve differences in variant interpretations submitted to ClinVar. CLINVAR

33939675 ↗ Genetic Variants in Patients With a Family History of Pancreatic Cancer: Impact of Multigene Panel Testing. CLINVAR

34197922 ↗ Use of Treatment-Focused Tumor Sequencing to Screen for Germline Cancer Predisposition. CLINVAR

28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR