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.1270G>A (p.Ala424Thr)

CA028060

220203 (ClinVar)

Gene: MLH1
Condition: colorectal cancer, hereditary nonpolyposis, type 2
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: d6dacd95-24ed-4be6-9365-fa1f75132945
Approved on: 2024-10-11
Published on: 2024-10-11

HGVS expressions

NM_000249.4:c.1270G>A
NM_000249.4(MLH1):c.1270G>A (p.Ala424Thr)
NC_000003.12:g.37025868G>A
CM000665.2:g.37025868G>A
NC_000003.11:g.37067359G>A
CM000665.1:g.37067359G>A
NC_000003.10:g.37042363G>A
NG_007109.2:g.37519G>A
ENST00000413740.2:c.1270G>A
ENST00000429117.6:c.976G>A
ENST00000450420.6:c.1270G>A
ENST00000456676.7:c.1270G>A
ENST00000458009.6:c.*171G>A
ENST00000492474.6:c.547G>A
ENST00000616768.6:c.1270G>A
ENST00000673673.2:c.1270G>A
ENST00000231790.8:c.1270G>A
ENST00000413212.2:c.*188G>A
ENST00000432299.6:c.*1102G>A
ENST00000441265.6:c.547G>A
ENST00000442249.6:n.1078G>A
ENST00000447829.6:c.*381G>A
ENST00000539477.6:c.547G>A
ENST00000616768.5:c.307G>A
ENST00000673673.1:c.1223G>A
ENST00000673713.1:n.1394G>A
ENST00000673715.1:c.1270G>A
ENST00000673889.1:n.652G>A
ENST00000673897.1:c.*1062G>A
ENST00000673899.1:c.678-2916G>A
ENST00000673947.1:c.*1410G>A
ENST00000673972.1:c.*1148G>A
ENST00000673990.1:n.1161G>A
ENST00000674019.1:c.547G>A
ENST00000674107.1:n.1118G>A
ENST00000674111.1:c.1270G>A
ENST00000231790.6:c.1270G>A
ENST00000413212.1:c.345G>A
ENST00000435176.5:c.976G>A
ENST00000447829.5:c.557G>A
ENST00000455445.6:c.547G>A
ENST00000456676.6:c.1245G>A
ENST00000458009.5:c.457G>A
ENST00000458205.6:c.547G>A
ENST00000536378.5:c.547G>A
ENST00000539477.5:c.547G>A
ENST00000616768.4:c.38G>A
NM_000249.3:c.1270G>A
NM_001167617.1:c.976G>A
NM_001167618.1:c.547G>A
NM_001167619.1:c.547G>A
NM_001258271.1:c.1270G>A
NM_001258273.1:c.547G>A
NM_001258274.1:c.547G>A
NM_001167617.2:c.976G>A
NM_001167618.2:c.547G>A
NM_001167619.2:c.547G>A
NM_001258274.2:c.547G>A
NM_001354615.1:c.547G>A
NM_001354616.1:c.547G>A
NM_001354617.1:c.547G>A
NM_001354618.1:c.547G>A
NM_001354619.1:c.547G>A
NM_001354620.1:c.976G>A
NM_001354621.1:c.247G>A
NM_001354622.1:c.247G>A
NM_001354623.1:c.247G>A
NM_001354624.1:c.196G>A
NM_001354625.1:c.196G>A
NM_001354626.1:c.196G>A
NM_001354627.1:c.196G>A
NM_001354628.1:c.1270G>A
NM_001354629.1:c.1171G>A
NM_001354630.1:c.1270G>A
NM_001167617.3:c.976G>A
NM_001167618.3:c.547G>A
NM_001167619.3:c.547G>A
NM_001258271.2:c.1270G>A
NM_001258273.2:c.547G>A
NM_001258274.3:c.547G>A
NM_001354615.2:c.547G>A
NM_001354616.2:c.547G>A
NM_001354617.2:c.547G>A
NM_001354618.2:c.547G>A
NM_001354619.2:c.547G>A
NM_001354620.2:c.976G>A
NM_001354621.2:c.247G>A
NM_001354622.2:c.247G>A
NM_001354623.2:c.247G>A
NM_001354624.2:c.196G>A
NM_001354625.2:c.196G>A
NM_001354626.2:c.196G>A
NM_001354627.2:c.196G>A
NM_001354628.2:c.1270G>A
NM_001354629.2:c.1171G>A
NM_001354630.2:c.1270G>A
More

Uncertain Significance

Met criteria codes 1
BP4
Not Met criteria codes 1
PM2

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.1270G>A variant in MLH1 is a missense variant predicted to cause substitution of Alanin by Threonin at amino acid 424 (p.Ala424Thr). The prior probability of this variant is 0,10 which fullfills the criteria of BP4 (missense variant with MAPP+PolyPhen-2 prior probability for pathogenicity <0.11 as per http://priors.hci.utah.edu/PRIORS). The Frequency of this variant in gnomAD V4.1.0 Grpmax AF = 0.00005797 (0.005797%), which is higher than the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP threshold (<1 in 50,000 alleles) for PM2_supporting, and therefore PM2_supporting is not met. Due to conflicting 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: PM2_SUP, BP4 (VCEP specifications version 1)
Met criteria codes
BP4
Prior probability 0,10; missense variant with MAPP+PolyPhen-2 prior probability for pathogenicity <0.11 as per http://priors.hci.utah.edu/PRIORS (BP4 met)
Not Met criteria codes
PM2
The frequency of NM_000249.4(MLH1):c.1270G>A (p.Ala424Thr) is 0.000009 (in the non-cancer dataset of gnomAD v2.2.1) which is lower than the MLH1-VCEP threshold of ≤ 0.00002. Update: GnomAD v4.1 Grpmax AF = 0.00005797 > 0.00002 (PM2_Supporting is not met)
Curation History
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