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.2042C>T (p.Ala681Val)

CA008313

90011 (ClinVar)

Gene: MLH1
Condition: Lynch syndrome 1
Inheritance Mode: Autosomal dominant inheritance
UUID: 0f212932-d140-4720-84c0-9bb167ebb160
Approved on: 2024-09-19
Published on: 2024-10-11

HGVS expressions

NM_000249.4:c.2042C>T
NM_000249.4(MLH1):c.2042C>T (p.Ala681Val)
NC_000003.12:g.37048956C>T
CM000665.2:g.37048956C>T
NC_000003.11:g.37090447C>T
CM000665.1:g.37090447C>T
NC_000003.10:g.37065451C>T
NG_007109.2:g.60607C>T
ENST00000413740.2:c.1668-1530C>T
ENST00000429117.6:c.1748C>T
ENST00000450420.6:c.1559-1530C>T
ENST00000456676.7:c.1896+1273C>T
ENST00000492474.6:c.1319C>T
ENST00000616768.6:c.1949C>T
ENST00000673673.2:c.1877C>T
ENST00000231790.8:c.2042C>T
ENST00000413212.2:c.*960C>T
ENST00000432299.6:c.*1874C>T
ENST00000447829.6:c.*1153C>T
ENST00000539477.6:c.1319C>T
ENST00000616768.5:c.986C>T
ENST00000673673.1:c.1830C>T
ENST00000673741.1:n.1076C>T
ENST00000673889.1:n.1424C>T
ENST00000673897.1:c.*1834C>T
ENST00000673899.1:c.1310C>T
ENST00000673947.1:c.*2182C>T
ENST00000673972.1:c.*1920C>T
ENST00000674019.1:c.1319C>T
ENST00000674111.1:c.*271C>T
ENST00000674125.1:n.753C>T
ENST00000231790.6:c.2042C>T
ENST00000413740.1:c.291-1530C>T
ENST00000435176.5:c.1748C>T
ENST00000450420.5:c.182-1530C>T
ENST00000455445.6:c.1319C>T
ENST00000456676.6:c.1871+1273C>T
ENST00000458205.6:c.1319C>T
ENST00000536378.5:c.1319C>T
ENST00000539477.5:c.1319C>T
NM_000249.3:c.2042C>T
NM_001167617.1:c.1748C>T
NM_001167618.1:c.1319C>T
NM_001167619.1:c.1319C>T
NM_001258271.1:c.1896+1273C>T
NM_001258273.1:c.1319C>T
NM_001258274.1:c.1319C>T
NM_001167617.2:c.1748C>T
NM_001167618.2:c.1319C>T
NM_001167619.2:c.1319C>T
NM_001258274.2:c.1319C>T
NM_001354615.1:c.1319C>T
NM_001354616.1:c.1319C>T
NM_001354617.1:c.1319C>T
NM_001354618.1:c.1319C>T
NM_001354619.1:c.1319C>T
NM_001354620.1:c.1748C>T
NM_001354621.1:c.1019C>T
NM_001354622.1:c.1019C>T
NM_001354623.1:c.1019C>T
NM_001354624.1:c.968C>T
NM_001354625.1:c.968C>T
NM_001354626.1:c.968C>T
NM_001354627.1:c.968C>T
NM_001354628.1:c.1949C>T
NM_001354629.1:c.1943C>T
NM_001354630.1:c.1877C>T
NM_001167617.3:c.1748C>T
NM_001167618.3:c.1319C>T
NM_001167619.3:c.1319C>T
NM_001258271.2:c.1896+1273C>T
NM_001258273.2:c.1319C>T
NM_001258274.3:c.1319C>T
NM_001354615.2:c.1319C>T
NM_001354616.2:c.1319C>T
NM_001354617.2:c.1319C>T
NM_001354618.2:c.1319C>T
NM_001354619.2:c.1319C>T
NM_001354620.2:c.1748C>T
NM_001354621.2:c.1019C>T
NM_001354622.2:c.1019C>T
NM_001354623.2:c.1019C>T
NM_001354624.2:c.968C>T
NM_001354625.2:c.968C>T
NM_001354626.2:c.968C>T
NM_001354627.2:c.968C>T
NM_001354628.2:c.1949C>T
NM_001354629.2:c.1943C>T
NM_001354630.2:c.1877C>T

Uncertain Significance

Met criteria codes 2
PP4_Strong PM2_Supporting
Not Met criteria codes 1
PP3

Evidence Links 0

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: c.2042C>T variant in MLH1 is a missense variant predicted to cause substitution of Alanin by Valin at amino acid 681 (p.Ala681Val). This variant has been detected in at least three patient with colorectal or endometrial MSI-H / loss MLH1/PMS2 tumours (PP4_Strong). This variant is absent in gnomAD v2.1.1 using the non-cancer dataset and gnomAD v4.1 (PM2_Supporting). Due to insufficient evidence, this variant is classified as a variant of uncertain significance for Lynch-Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/ Polyposis VCEP: PP4_STR, PM2_SUP (VCEP specifications version 1).
Met criteria codes
PP4_Strong
At least three patient with colorectal or endometrial MSI-H tumours (PP4).
PM2_Supporting
Absent in gnomAD v2.1.1 using the non-cancer dataset and gnomAD v4.1
Not Met criteria codes
PP3
Missense variant with MAPP/PP2 score=0.20.
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.
¤ Powered by BCM's Genboree.