Classification rationale

PM2 BP4 Uncertain Significance - Conflicting Evidence

MLH1 c.1637A>G

HCI prior probability for pathogenicity is 0.0023, meeting BP4_Supporting per InSiGHT VCEP v2.0.0 (threshold <0.11). REVEL (0.469) and BayesDel (-0.0407) are consistent with a benign in silico profile.¹ Extremely rare in gnomAD v4.1 (grpmax FAF = 1.24e-06; 6/1,613,836 alleles, 0 homozygotes), meeting PM2_Supporting per InSiGHT VCEP v2.0.0 (threshold <0.00002). Absent from gnomAD-Canada v1.0.² This variant has been reported in ClinVar (Variation ID: 127617) with submissions of Uncertain Significance (10 clinical laboratories), Benign (1), and Likely Benign (1); no expert panel classification is available.³ NM_000249.4:c.1637A>G (p.Lys546Arg) was observed in 1 of 711 patients with hereditary breast cancer in a Russian case-control study (PMID:32547938); no variant-specific MSI, IHC, or functional data were reported.⁴

PM2 + BP4 → Uncertain Significance - Conflicting Evidence

1 hci_priorrevelbayesdel

2 gnomad_v4 ↗gnomad_canada ↗

3 clinvar ↗

4 PMID:32547938 ↗

Gene diagram · NM_000249.4 · variants mapped to exon structure

MLH1 NM_000249.4

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= 3.71785e-06; MAF= 0.00037%, 6/1613836 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 1.33529e-05; MAF= 0.00134%, 1/74890 alleles, homozygotes = 0); grpmax FAF= 1.24e-06.

v2.1

This variant is present in gnomAD v2.1 (AF= 7.95805e-06; MAF= 0.00080%, 2/251318 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.75982e-05; MAF= 0.00176%, 2/113648 alleles, homozygotes = 0); grpmax FAF= 2.92e-06.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.00037% · 6 / 1,613,836
0 hom · FAF 0.00012%

African/African American 1 / 74,890	0.0013%
European (non-Finnish) 5 / 1,179,892	0.00042%

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

gnomAD v2.1

0.0008% · 2 / 251,318
0 hom · FAF 0.00029%

European (non-Finnish)

2 / 113,648

0.0018%

+ 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 (9 clinical laboratories) and as Uncertain Significance (1 clinical laboratory) and as Benign (1 clinical laboratory) and as Likely benign (1 clinical laboratory). (ClinVarID = 127617)

ClinVar ↗

In silico

SpliceAI predicts possible splice impact for this variant (max delta score = 0.36). REVEL score = 0.469. BayesDel score = -0.0406917. HCI prior probability for pathogenicity = 0.0023. MAPP score = 3.83. Custom PP2 score = 0.016.

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. MLH1, a DNA mismatch repair protein, is recurrently altered by deletion and mutation in various cancer types.

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

26467025 ↗ A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders. CLINVAR

32547938 ↗ Lynch Syndrome Germline Mutations in Breast Cancer: Next Generation Sequencing Case-Control Study of 1,263 Participants. CLINVAR

32832836 ↗ Pathogenic Variants in Cancer Predisposition Genes and Prostate Cancer Risk in Men of African Ancestry. CLINVAR

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

23535968 ↗ Informing family members of individuals with Lynch syndrome: a guideline for clinical geneticists. CLINVAR

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

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