Variant: NM_000249.4(MLH1):c.1646T>C (p.Leu549Pro)

CA006221

89816 (ClinVar)

Gene: MLH1

Condition: Lynch syndrome 1

Inheritance Mode: Autosomal dominant inheritance

UUID: 5f4e45d9-90b4-4312-9150-265a2d45c21c

Approved on: 2024-09-19

Published on: 2024-10-11

HGVS expressions

NM_000249.4:c.1646T>C
NM_000249.4(MLH1):c.1646T>C (p.Leu549Pro)
NC_000003.12:g.37040273T>C
CM000665.2:g.37040273T>C
NC_000003.11:g.37081764T>C
CM000665.1:g.37081764T>C
NC_000003.10:g.37056768T>C
NG_007109.2:g.51924T>C
ENST00000413740.2:c.1646T>C
ENST00000429117.6:c.1352T>C
ENST00000450420.6:c.1559-10213T>C
ENST00000456676.7:c.1646T>C
ENST00000492474.6:c.923T>C
ENST00000616768.6:c.1646T>C
ENST00000673673.2:c.1646T>C
ENST00000231790.8:c.1646T>C
ENST00000413212.2:c.*564T>C
ENST00000432299.6:c.*1478T>C
ENST00000441265.6:c.923T>C
ENST00000447829.6:c.*757T>C
ENST00000539477.6:c.923T>C
ENST00000616768.5:c.683T>C
ENST00000673673.1:c.1599T>C
ENST00000673715.1:c.1646T>C
ENST00000673889.1:n.1028T>C
ENST00000673897.1:c.*1438T>C
ENST00000673899.1:c.914T>C
ENST00000673947.1:c.*1786T>C
ENST00000673972.1:c.*1524T>C
ENST00000673990.1:n.1537T>C
ENST00000674019.1:c.923T>C
ENST00000674111.1:c.1646T>C
ENST00000674125.1:n.357T>C
ENST00000231790.6:c.1646T>C
ENST00000413740.1:c.269T>C
ENST00000435176.5:c.1352T>C
ENST00000450420.5:c.182-10213T>C
ENST00000455445.6:c.923T>C
ENST00000456676.6:c.1621T>C
ENST00000458205.6:c.923T>C
ENST00000536378.5:c.923T>C
ENST00000539477.5:c.923T>C
ENST00000616768.4:c.414T>C
NM_000249.3:c.1646T>C
NM_001167617.1:c.1352T>C
NM_001167618.1:c.923T>C
NM_001167619.1:c.923T>C
NM_001258271.1:c.1646T>C
NM_001258273.1:c.923T>C
NM_001258274.1:c.923T>C
NM_001167617.2:c.1352T>C
NM_001167618.2:c.923T>C
NM_001167619.2:c.923T>C
NM_001258274.2:c.923T>C
NM_001354615.1:c.923T>C
NM_001354616.1:c.923T>C
NM_001354617.1:c.923T>C
NM_001354618.1:c.923T>C
NM_001354619.1:c.923T>C
NM_001354620.1:c.1352T>C
NM_001354621.1:c.623T>C
NM_001354622.1:c.623T>C
NM_001354623.1:c.623T>C
NM_001354624.1:c.572T>C
NM_001354625.1:c.572T>C
NM_001354626.1:c.572T>C
NM_001354627.1:c.572T>C
NM_001354628.1:c.1646T>C
NM_001354629.1:c.1547T>C
NM_001354630.1:c.1646T>C
NM_001167617.3:c.1352T>C
NM_001167618.3:c.923T>C
NM_001167619.3:c.923T>C
NM_001258271.2:c.1646T>C
NM_001258273.2:c.923T>C
NM_001258274.3:c.923T>C
NM_001354615.2:c.923T>C
NM_001354616.2:c.923T>C
NM_001354617.2:c.923T>C
NM_001354618.2:c.923T>C
NM_001354619.2:c.923T>C
NM_001354620.2:c.1352T>C
NM_001354621.2:c.623T>C
NM_001354622.2:c.623T>C
NM_001354623.2:c.623T>C
NM_001354624.2:c.572T>C
NM_001354625.2:c.572T>C
NM_001354626.2:c.572T>C
NM_001354627.2:c.572T>C
NM_001354628.2:c.1646T>C
NM_001354629.2:c.1547T>C
NM_001354630.2:c.1646T>C

Likely Pathogenic

• Met criteria codes: PM2_Supporting PP1_Strong PP3_Moderate

Expert Panel

InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP

Criteria Specification Information

Criteria Specification: ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MLH1 Version 1.0.0

Evidence submitted by expert panel

InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP

This NM_000249.4:c.1646T>C variant in MLH1 has been reported to segregate with disease in ≥2 families (PP1_strong). The missense variant has a prior probability for pathogenicity >0.81 (MAPP/PP2:0.82) (PP3_moderate). The variant is not reported in gnomAD v2.1.1 (non-cancer) and gnomAD v4.1 datasets (PM2_supporting). Therefore, this variant is classified as likely pathogenic. (VCEP specifications version 1)

Met criteria codes

• PM2_Supporting: The variant is absent in gnomAD using the non-cancer dataset (v2.1.1) and gnomAD v4.1 dataset
• PP1_Strong: This variant has been reported to segregate with disease in ≥2 families.
• PP3_Moderate: Missense variant with MAPP+PolyPhen-2 prior probability for pathogenicity >0.81 (MAPP/PP2:0.82). hci-priors.hci.utah.edu/PRIORS/