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 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 · 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