Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computed assertion could be determined for this classification!

Variant: NM_000249.4(MLH1):c.649C>T (p.Arg217Cys)

CA011361

90303 (ClinVar)

Gene: MLH1
Condition: Lynch syndrome 1
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: ae859af5-7294-46fd-aa10-21fb29d84c7e
Approved on: 2024-09-19
Published on: 2024-10-11

HGVS expressions

NM_000249.4:c.649C>T
NM_000249.4(MLH1):c.649C>T (p.Arg217Cys)
NC_000003.12:g.37012071C>T
CM000665.2:g.37012071C>T
NC_000003.11:g.37053562C>T
CM000665.1:g.37053562C>T
NC_000003.10:g.37028566C>T
NG_007109.2:g.23722C>T
ENST00000413740.2:c.649C>T
ENST00000429117.6:c.355C>T
ENST00000450420.6:c.649C>T
ENST00000456676.7:c.649C>T
ENST00000458009.6:c.649C>T
ENST00000492474.6:c.-75C>T
ENST00000616768.6:c.649C>T
ENST00000673673.2:c.649C>T
ENST00000231790.8:c.649C>T
ENST00000413212.2:c.-75C>T
ENST00000432299.6:c.*729C>T
ENST00000441265.6:c.-75C>T
ENST00000442249.6:n.664C>T
ENST00000447829.6:c.286C>T
ENST00000539477.6:c.-75C>T
ENST00000673673.1:c.602C>T
ENST00000673713.1:n.680C>T
ENST00000673715.1:c.649C>T
ENST00000673897.1:c.*441C>T
ENST00000673899.1:c.649C>T
ENST00000673947.1:c.*789C>T
ENST00000673972.1:c.*527C>T
ENST00000673990.1:n.634C>T
ENST00000674019.1:c.-75C>T
ENST00000674107.1:n.591C>T
ENST00000674111.1:c.649C>T
ENST00000231790.6:c.649C>T
ENST00000432299.5:c.*729C>T
ENST00000435176.5:c.355C>T
ENST00000441265.5:c.-75C>T
ENST00000447829.5:c.30C>T
ENST00000455445.6:c.-75C>T
ENST00000456676.6:c.624C>T
ENST00000457004.5:c.*428C>T
ENST00000458205.6:c.-75C>T
ENST00000536378.5:c.-75C>T
ENST00000539477.5:c.-75C>T
NM_000249.3:c.649C>T
NM_001167617.1:c.355C>T
NM_001167618.1:c.-75C>T
NM_001167619.1:c.-75C>T
NM_001258271.1:c.649C>T
NM_001258273.1:c.-75C>T
NM_001258274.1:c.-75C>T
NM_001167617.2:c.355C>T
NM_001167618.2:c.-75C>T
NM_001167619.2:c.-75C>T
NM_001258274.2:c.-75C>T
NM_001354615.1:c.-75C>T
NM_001354616.1:c.-75C>T
NM_001354617.1:c.-75C>T
NM_001354618.1:c.-75C>T
NM_001354619.1:c.-75C>T
NM_001354620.1:c.355C>T
NM_001354621.1:c.-168C>T
NM_001354622.1:c.-281C>T
NM_001354623.1:c.-281C>T
NM_001354624.1:c.-178C>T
NM_001354625.1:c.-178C>T
NM_001354626.1:c.-178C>T
NM_001354627.1:c.-178C>T
NM_001354628.1:c.649C>T
NM_001354629.1:c.550C>T
NM_001354630.1:c.649C>T
NM_001167617.3:c.355C>T
NM_001167618.3:c.-75C>T
NM_001167619.3:c.-75C>T
NM_001258271.2:c.649C>T
NM_001258273.2:c.-75C>T
NM_001258274.3:c.-75C>T
NM_001354615.2:c.-75C>T
NM_001354616.2:c.-75C>T
NM_001354617.2:c.-75C>T
NM_001354618.2:c.-75C>T
NM_001354619.2:c.-75C>T
NM_001354620.2:c.355C>T
NM_001354621.2:c.-168C>T
NM_001354622.2:c.-281C>T
NM_001354623.2:c.-281C>T
NM_001354624.2:c.-178C>T
NM_001354625.2:c.-178C>T
NM_001354626.2:c.-178C>T
NM_001354627.2:c.-178C>T
NM_001354628.2:c.649C>T
NM_001354629.2:c.550C>T
NM_001354630.2:c.649C>T
More

Benign

Met criteria codes 3
BP5 BS1 BS3

Evidence Links 1

Expert Panel

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

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP
The NM_000249.4(MLH1):c.649C>T (p.Arg217Cys) variant is a missense variant predicted to cause substitution of Arginine by Cystein at amino acid 217 (p.Arg217Cys). The allele frequency of the variant c.649C>T is 0.3% (PopMax Filtering AF 0.0037 in East Asian Population) for the total non-cancer dataset from gnomAD (v2.1.1), and gnomAD v4.1 Grpmax AF is 0.003970 which is higher than the ClinGen InSiGHT MMR VCEP threshold (≥ 0.001 or 0,1%) for BS1, and therefore meets this criterion (BS1). The CIMRA Functional Odds for Pathogenicity is 0.01 which is below the VCEP threshold of ≤ 0.052 (BS3 met). Also the variant has been detected in 2 or 3 tumours: CRC/Endometrial tumours with MSS and/or no loss of MMR protein expression and/or LS spectrum tumoursf with loss of MMR protein(s) that is inconsistent with the gene demonstrating genetic variation (BP5 met). In summary, this variant meets the criteria to be classified as benign for autosomal-dominant inherited Lynch syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP : criteria BS2, BS3 and BP5 applied. (VCEP specifications version 1)
Met criteria codes
BP5
ORCID: Zhang, Furihata 2001, (BP5 met)
BS1
The allele frequency of the variant NM_000249.4(MLH1):c.649C>T (p.Arg217Cys) is 0.3% (FAF 0.0037 in East Asian Population) for the total non-cancer dataset from gnomAD (v2.1.1) and gnomAD v4.1 Grpmax AF = 0.003970, which is higher than the ClinGen InSiGHT MMR VCEP threshold (≥ 0.001 or 0,1%) for BS1, and therefore meets this criterion (BS1).
BS3
CIMRA Functional Odds for Pathogenicity is 0.01 which is below the VCEP threshold of ≤ 0.052
CIMRA Functional Odds for Pathogenicity is 0.01 (Data_Sheet_1) PubMed:32849802
Curation History
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