Classification rationale

PM2 BP4 Uncertain Significance - Conflicting Evidence

MSH6 c.643G>C

NM_000179.3:c.643G>C (p.Val215Leu) is a missense variant in exon 4 of MSH6. It is extremely rare in population databases (gnomAD v4.1 AF=1.24e-06), meeting PM2_Supporting per the InSiGHT MSH6 VCEP v2.0.0 threshold of <0.00002.¹ Multiple in silico predictors support a benign effect: the MSH6-specific HCI prior probability for pathogenicity is 0.0008, meeting BP4_Supporting (threshold <0.11). REVEL (0.139) and BayesDel (-0.503783) are also consistent with a benign prediction. SpliceAI predicts no splicing impact (max delta 0.09).² No variant-specific functional data, segregation data, tumor phenotype data, or de novo observations are available for this variant. The variant has not been classified by the VCEP pilot program and no comparator missense changes at codon 215 have been established as pathogenic.³ This variant has been reported in ClinVar as Uncertain Significance by multiple clinical laboratories (ClinVar ID: 628619). Nine publications were reviewed; none mention NM_000179.3:c.643G>C.⁴

PM2 + BP4 → Uncertain Significance - Conflicting Evidence

1 gnomad_v4 ↗

2 hci_priorrevelbayesdelspliceai ↗

3 clinvar ↗vcep_functional_assay_svi_documentation_mmrvcep_vcep_pilot_variants_mmr

4 clinvar ↗

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

MSH6 NM_000179.3

Fetching transcript structure from UCSC…

Applied criteria · 2 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= 1.24163e-06; MAF= 0.00012%, 2/1610788 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 2.22727e-05; MAF= 0.00223%, 1/44898 alleles, homozygotes = 0).

v2.1

This variant is present in gnomAD v2.1 (AF= 4.05108e-06; MAF= 0.00041%, 1/246848 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.87737e-06; MAF= 0.00089%, 1/112646 alleles, homozygotes = 0).

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.00012% · 2 / 1,610,788
0 hom

East Asian 1 / 44,898	0.0022%
European (non-Finnish) 1 / 1,179,946	8.5e-05%

+ 8 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)

gnomAD v2.1

0.00041% · 1 / 246,848
0 hom

European (non-Finnish)

1 / 112,646

0.00089%

+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Uncertain significance (3 clinical laboratories) and as Uncertain Significance (1 clinical laboratory) and as Likely benign (1 clinical laboratory). (ClinVarID = 628619)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.09). REVEL score = 0.139. BayesDel score = -0.503783. HCI prior probability for pathogenicity = 0.0008. MAPP score = 2.5. Custom PP2 score = 0.0.

SpliceAI ↗

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.

OncoKB ↗

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.

COSMIC ↗ Hotspots ↗

Sources & reference links

9Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

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

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

28135145 ↗ Cancer Susceptibility Gene Mutations in Individuals With Colorectal Cancer. CLINVAR

23408351 ↗ Revised guidelines for the clinical management of Lynch syndrome (HNPCC): recommendations by a group of European experts. CLINVAR

24310308 ↗ ACMG technical standards and guidelines for genetic testing for inherited colorectal cancer (Lynch syndrome, familial adenomatous polyposis, and MYH-associated polyposis). CLINVAR

26389258 ↗ Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Versi 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

30267214 ↗ Rare loss of function variants in candidate genes and risk of colorectal cancer. CLINVAR

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