Classification rationale

PVS1PM2PP5 Pathogenic

MSH6 c.3261del

The MSH6 NM_000179.3:c.3261del (NP_000170.1:p.(Phe1088SerfsTer2)) variant has been observed in somatic cancers in COSMIC (COSV52273658, n=132) and has been reported in ClinVar as Pathogenic, including an expert-panel assertion.¹ This variant is present at extremely low frequency in population databases, with gnomAD v4.1 allele frequency 1.42855e-05 (23/1610026 alleles; grpmax FAF 7.65e-06), which is below the MSH6 VCEP PM2 threshold of 0.00002, and it is absent from gnomAD-Canada v1.0.² This frameshift deletion is predicted to truncate MSH6 at codon 1088, and the active MSH6 VCEP specification applies PVS1 at Very Strong strength to nonsense or frameshift variants introducing a premature termination codon at or before codon 1341.³

PVS1 + PM2 + PP5 → Pathogenic

1 clinvar ↗

2 cspec ↗gnomad_v4 ↗gnomad_canada ↗gnomad_v2 ↗

3 cspec ↗pvs1_gene_contextpvs1_variant_assessment

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

MSH6 NM_000179.3

Fetching transcript structure from UCSC…

Applied criteria · 3 applied · 11 assessed

Applied · 3

Strength Supporting Moderate Strong Very strong

✓

PVS1 very strong Pathogenic

This variant is a frameshift deletion predicted to produce p.(Phe1088SerfsTer2). Under the MSH6 VCEP specification, nonsense/frameshift variants introducing a premature termination codon at or before codon 1341 meet PVS1 at Very Strong strength; this variant truncates the protein at codon 1088 and loss of function is an established disease mechanism for MSH6.

NM_000179.3:c.3261del predicts NP_000170.1:p.(Phe1088SerfsTer2)MSH6 VCEP PVS1 Very Strong applies to nonsense/frameshift variants with PTC at or before codon 1341Loss of function is an established MSH6 disease mechanism in the active VCEP framework

cspec ↗

✓

PM2 supporting Pathogenic

This variant is present at extremely low frequency in population databases. In gnomAD v4.1, the allele frequency is 1.42855e-05 (23/1610026 alleles) with grpmax FAF 7.65e-06, which is below the MSH6 VCEP PM2 threshold of 0.00002 (<1 in 50,000 alleles), and it is absent from gnomAD-Canada v1.0.

gnomAD v4.1 total AF 1.42855e-0523/1610026 alleles0 homozygotes

cspec ↗gnomad_v4 ↗gnomad_canada ↗gnomad_v2 ↗

✓

PP5 supporting Pathogenic

Expert panel International Society for Gastrointestinal Hereditary Tumours (InSiGHT) classified as Pathogenic.

ClinVar expert panel classification

cspec ↗clinvar ↗

Assessed · not applied

Pathogenic

PS2 No confirmed de novo occurrence with verified parentage was identified.

PS3 No directly reviewed calibrated functional assay or RNA evidence demonstrating an abnormal MSH6 effect for this exact variant was identified for PS3 assignment.

PM3 No phase-confirmed biallelic observations or PM3 point-based evidence were identified.

PP1 No segregation dataset with a combined Bayes likelihood ratio meeting PP1 thresholds was identified.

PP4 No directly reviewed tumor MSI or mismatch-repair immunohistochemistry data specific enough to assign PP4 were identified.

Benign

BA1 This variant does not meet BA1 because the gnomAD v4.1 filtering allele frequency is far below the MSH6 VCEP BA1 threshold of 0.0022 (0.22%).

BS1 This variant does not meet BS1 because the gnomAD v4.1 filtering allele frequency is below the MSH6 VCEP BS1 range of 0.00022 to <0.0022.

BS2 No confirmed in trans co-occurrence with a known pathogenic MSH6 variant in an individual meeting the VCEP age and CMMRD exclusion requirements was identified.

BS3 No directly reviewed calibrated functional assay or RNA study demonstrating normal MSH6 function for this variant was identified.

BS4 No segregation dataset with a combined Bayes likelihood ratio supporting lack of co-segregation was identified.

BP5 No tumor series showing repeated mismatch between the tumor phenotype and the gene harboring this variant was identified.

N/A · 14 PS1 · PS4 · PM1 · PM4 · PM5 · PM6 · PP2 · PP3 · BP1 · BP2 · BP3 · BP4 · BP6 · BP7

Research & evidence

Population frequency · supports pathogenic

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 1.42855e-05; MAF= 0.00143%, 23/1610026 alleles, homozygotes = 0) and has highest observed frequency in the European (Finnish) population (AF= 6.27825e-05; MAF= 0.00628%, 4/63712 alleles, homozygotes = 0); grpmax FAF= 7.65e-06.

v2.1

This variant is present in gnomAD v2.1 (AF= 1.42412e-05; MAF= 0.00142%, 4/280876 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 9.68804e-05; MAF= 0.00969%, 1/10322 alleles, homozygotes = 0).

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.0014% · 23 / 1,610,026
0 hom · FAF 0.00076%

European (Finnish) 4 / 63,712	0.0063%
East Asian 1 / 44,802	0.0022%
Remaining individuals 1 / 62,362	0.0016%
African/African American 1 / 74,238	0.0013%
European (non-Finnish) 15 / 1,177,722	0.0013%
South Asian 1 / 90,950	0.0011%

+ 4 not observed (Admixed American, Amish, Middle Eastern, Ashkenazi Jewish)

gnomAD v2.1

0.0014% · 4 / 280,876
0 hom

Ashkenazi Jewish 1 / 10,322	0.0097%
African/African American 1 / 24,758	0.004%
European (Finnish) 1 / 25,028	0.004%
European (non-Finnish) 1 / 127,934	0.00078%

+ 4 not observed (Admixed American, East Asian, 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 Pathogenic (31 clinical laboratories) and as pathogenic (1 clinical laboratory) and as Pathogenic by International Society for Gastrointestinal Hereditary Tumours (InSiGHT) (expert panel). (ClinVarID = 89363)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04).

SpliceAI ↗

Functional Likely Oncogenic

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV52273658, n = 132 times).

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 · 10 PMIDs not cited in assessment

21674763 ↗ High-grade brain tumors in siblings with biallelic MSH6 mutations. ONCOKB

15837969 ↗ Molecular analysis of familial endometrial carcinoma: a manifestation of hereditary nonpolyposis colorectal cancer or a separate syndrome? ONCOKB

15236168 ↗ Cancer risk in hereditary nonpolyposis colorectal cancer due to MSH6 mutations: impact on counseling and surveillance. CLINVAR

15483016 ↗ Lower incidence of colorectal cancer and later age of disease onset in 27 families with pathogenic MSH6 germline mutations compared with families with MLH1 or MSH2 mutations: the German Hereditary Nonpolyposis Colorectal Cancer Consortium. CLINVAR

17117178 ↗ Very low prevalence of germline MSH6 mutations in hereditary non-polyposis colorectal cancer suspected patients with colorectal cancer without microsatellite instability. CLINVAR

19526325 ↗ Screening for germline mutations of MLH1, MSH2, MSH6 and PMS2 genes in Slovenian colorectal cancer patients: implications for a population specific detection strategy of Lynch syndrome. CLINVAR

20007843 ↗ Combined iPLEX and TaqMan assays to screen for 45 common mutations in Lynch syndrome and FAP patients. CLINVAR

20028993 ↗ Risks of Lynch syndrome cancers for MSH6 mutation carriers. CLINVAR

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

32720330 ↗ Fitting a naturally scaled point system to the ACMG/AMP variant classification guidelines. CLINVAR

Re-run this variant?