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.1963A>T (p.Ile655Phe)

CA031690

1000222 (ClinVar)

Gene: MLH1
Condition: Lynch syndrome
Inheritance Mode: Autosomal dominant inheritance
UUID: c9484e16-2cdc-4101-bee9-f16cd53d1b92
Approved on: 2024-09-19
Published on: 2024-10-11

HGVS expressions

NM_000249.4:c.1963A>T
NM_000249.4(MLH1):c.1963A>T (p.Ile655Phe)
NC_000003.12:g.37048583A>T
CM000665.2:g.37048583A>T
NC_000003.11:g.37090074A>T
CM000665.1:g.37090074A>T
NC_000003.10:g.37065078A>T
NG_007109.2:g.60234A>T
ENST00000413740.2:c.1668-1903A>T
ENST00000429117.6:c.1669A>T
ENST00000450420.6:c.1559-1903A>T
ENST00000456676.7:c.1896+900A>T
ENST00000492474.6:c.1240A>T
ENST00000616768.6:c.1897-321A>T
ENST00000673673.2:c.1798A>T
ENST00000231790.8:c.1963A>T
ENST00000413212.2:c.*881A>T
ENST00000432299.6:c.*1795A>T
ENST00000447829.6:c.*1074A>T
ENST00000539477.6:c.1240A>T
ENST00000616768.5:c.934-321A>T
ENST00000673673.1:c.1751A>T
ENST00000673741.1:n.997A>T
ENST00000673889.1:n.1345A>T
ENST00000673897.1:c.*1755A>T
ENST00000673899.1:c.1231A>T
ENST00000673947.1:c.*2103A>T
ENST00000673972.1:c.*1841A>T
ENST00000674019.1:c.1240A>T
ENST00000674111.1:c.*192A>T
ENST00000674125.1:n.674A>T
ENST00000231790.6:c.1963A>T
ENST00000413740.1:c.291-1903A>T
ENST00000435176.5:c.1669A>T
ENST00000450420.5:c.182-1903A>T
ENST00000455445.6:c.1240A>T
ENST00000456676.6:c.1871+900A>T
ENST00000458205.6:c.1240A>T
ENST00000536378.5:c.1240A>T
ENST00000539477.5:c.1240A>T
NM_000249.3:c.1963A>T
NM_001167617.1:c.1669A>T
NM_001167618.1:c.1240A>T
NM_001167619.1:c.1240A>T
NM_001258271.1:c.1896+900A>T
NM_001258273.1:c.1240A>T
NM_001258274.1:c.1240A>T
NM_001167617.2:c.1669A>T
NM_001167618.2:c.1240A>T
NM_001167619.2:c.1240A>T
NM_001258274.2:c.1240A>T
NM_001354615.1:c.1240A>T
NM_001354616.1:c.1240A>T
NM_001354617.1:c.1240A>T
NM_001354618.1:c.1240A>T
NM_001354619.1:c.1240A>T
NM_001354620.1:c.1669A>T
NM_001354621.1:c.940A>T
NM_001354622.1:c.940A>T
NM_001354623.1:c.940A>T
NM_001354624.1:c.889A>T
NM_001354625.1:c.889A>T
NM_001354626.1:c.889A>T
NM_001354627.1:c.889A>T
NM_001354628.1:c.1897-321A>T
NM_001354629.1:c.1864A>T
NM_001354630.1:c.1798A>T
NM_001167617.3:c.1669A>T
NM_001167618.3:c.1240A>T
NM_001167619.3:c.1240A>T
NM_001258271.2:c.1896+900A>T
NM_001258273.2:c.1240A>T
NM_001258274.3:c.1240A>T
NM_001354615.2:c.1240A>T
NM_001354616.2:c.1240A>T
NM_001354617.2:c.1240A>T
NM_001354618.2:c.1240A>T
NM_001354619.2:c.1240A>T
NM_001354620.2:c.1669A>T
NM_001354621.2:c.940A>T
NM_001354622.2:c.940A>T
NM_001354623.2:c.940A>T
NM_001354624.2:c.889A>T
NM_001354625.2:c.889A>T
NM_001354626.2:c.889A>T
NM_001354627.2:c.889A>T
NM_001354628.2:c.1897-321A>T
NM_001354629.2:c.1864A>T
NM_001354630.2:c.1798A>T
More

Uncertain Significance

Met criteria codes 2
BP4 PM2_Supporting
Not Met criteria codes 2
BP5 PVS1

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 MLH1 c.1963A>T variant is predicted as a missense variant, p.(Ile655Phe). It is extremely rare (<1 in 50,000 alleles) in gnomAD v.2.1.1 using the noncancer dataset and in gnomAD v4.1. Its MAPP+PolyPhen-2 prior probability for pathogenicity is <0.11 as per http://priors.hci.utah.edu/PRIORS. Therefore, this variant is classified as a variant of unknown significance. (VCEP specifications version 1)
Met criteria codes
BP4
Prior_utah (MAPP/PP2) = 0.001570797991008 which is < than 0.11. Moreover, it is not predicetd to affect splicing (max value SpliceAI 0and Prior_utah_splicing_de_novo = 0.02).
PM2_Supporting
PM2_supporting is assigned because the variant is observed at 4e-06 frequency (update: gnomAD v4.1 AF = 6.842e-7)
Not Met criteria codes
BP5
1 iIndividual in Insight database dx with sigmod cancer MSI-L/IHC normal
PVS1
PVS1 does not apply for this missense variant.
Curation History
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.