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.1732-19T>A

CA006607

36543 (ClinVar)

Gene: MLH1
Condition: Lynch syndrome 1
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: f92806f3-4049-46df-a8ba-f6011337b5c7
Approved on: 2024-09-19
Published on: 2024-10-10

HGVS expressions

NM_000249.4:c.1732-19T>A
NM_000249.4(MLH1):c.1732-19T>A
NC_000003.12:g.37047500T>A
CM000665.2:g.37047500T>A
NC_000003.11:g.37088991T>A
CM000665.1:g.37088991T>A
NC_000003.10:g.37063995T>A
NG_007109.2:g.59151T>A
ENST00000413740.2:c.1668-2986T>A
ENST00000429117.6:c.1438-19T>A
ENST00000450420.6:c.1559-2986T>A
ENST00000456676.7:c.1732-19T>A
ENST00000492474.6:c.1009-19T>A
ENST00000616768.6:c.1732-19T>A
ENST00000673673.2:c.1732-1017T>A
ENST00000231790.8:c.1732-19T>A
ENST00000413212.2:c.*650-19T>A
ENST00000432299.6:c.*1564-19T>A
ENST00000441265.6:c.945-19T>A
ENST00000447829.6:c.*843-19T>A
ENST00000539477.6:c.1009-19T>A
ENST00000616768.5:c.769-19T>A
ENST00000673673.1:c.1685-1017T>A
ENST00000673715.1:c.1732-19T>A
ENST00000673741.1:n.747T>A
ENST00000673889.1:n.1114-19T>A
ENST00000673897.1:c.*1524-19T>A
ENST00000673899.1:c.1000-19T>A
ENST00000673947.1:c.*1872-19T>A
ENST00000673972.1:c.*1610-19T>A
ENST00000673990.1:n.1623-19T>A
ENST00000674019.1:c.1009-19T>A
ENST00000674111.1:c.1668-19T>A
ENST00000674125.1:n.443-19T>A
ENST00000231790.6:c.1732-19T>A
ENST00000413740.1:c.291-2986T>A
ENST00000435176.5:c.1438-19T>A
ENST00000450420.5:c.182-2986T>A
ENST00000455445.6:c.1009-19T>A
ENST00000456676.6:c.1707-19T>A
ENST00000458205.6:c.1009-19T>A
ENST00000536378.5:c.1009-19T>A
ENST00000539477.5:c.1009-19T>A
ENST00000616768.4:c.500-19T>A
NM_000249.3:c.1732-19T>A
NM_001167617.1:c.1438-19T>A
NM_001167618.1:c.1009-19T>A
NM_001167619.1:c.1009-19T>A
NM_001258271.1:c.1732-19T>A
NM_001258273.1:c.1009-19T>A
NM_001258274.1:c.1009-19T>A
NM_001167617.2:c.1438-19T>A
NM_001167618.2:c.1009-19T>A
NM_001167619.2:c.1009-19T>A
NM_001258274.2:c.1009-19T>A
NM_001354615.1:c.1009-19T>A
NM_001354616.1:c.1009-19T>A
NM_001354617.1:c.1009-19T>A
NM_001354618.1:c.1009-19T>A
NM_001354619.1:c.1009-19T>A
NM_001354620.1:c.1438-19T>A
NM_001354621.1:c.709-19T>A
NM_001354622.1:c.709-19T>A
NM_001354623.1:c.709-19T>A
NM_001354624.1:c.658-19T>A
NM_001354625.1:c.658-19T>A
NM_001354626.1:c.658-19T>A
NM_001354627.1:c.658-19T>A
NM_001354628.1:c.1732-19T>A
NM_001354629.1:c.1633-19T>A
NM_001354630.1:c.1732-1017T>A
NM_001167617.3:c.1438-19T>A
NM_001167618.3:c.1009-19T>A
NM_001167619.3:c.1009-19T>A
NM_001258271.2:c.1732-19T>A
NM_001258273.2:c.1009-19T>A
NM_001258274.3:c.1009-19T>A
NM_001354615.2:c.1009-19T>A
NM_001354616.2:c.1009-19T>A
NM_001354617.2:c.1009-19T>A
NM_001354618.2:c.1009-19T>A
NM_001354619.2:c.1009-19T>A
NM_001354620.2:c.1438-19T>A
NM_001354621.2:c.709-19T>A
NM_001354622.2:c.709-19T>A
NM_001354623.2:c.709-19T>A
NM_001354624.2:c.658-19T>A
NM_001354625.2:c.658-19T>A
NM_001354626.2:c.658-19T>A
NM_001354627.2:c.658-19T>A
NM_001354628.2:c.1732-19T>A
NM_001354629.2:c.1633-19T>A
NM_001354630.2:c.1732-1017T>A
More

Benign

Met criteria codes 2
BA1 BS3
Not Met criteria codes 24
PS1 PS2 PS3 PS4 PVS1 PP1 PP2 PP3 PP4 PM1 PM3 PM5 PM4 PM6 PM2 BS1 BS4 BS2 BP5 BP7 BP4 BP3 BP1 BP2

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
NM_000249.4(MLH1):c.1732-19T>A is an intronic variant for which the gnomAD filtering allele frequency (African/African American) is 2.8% and gnomAD v4.1 Grpmax AF is 2.898%, meeting BA1 criteria according to the Maximum Credible Allele Frequency (MCAF) cutoffs for MLH1. There was also no impact on splicing in laboratory assays using nonsense-mediated decay inhibition (PMID: 27629256). In summary, this variant meets the criteria to be classified as benign for Lynch Syndrome, based on the MMR gene specific ACMG/AMP criteria established by the ClinGen InSiGHT Hereditary Colorectal Cancer/ Polyposis VCEP: BA1 and BS3 (VCEP specifications version 1)
Met criteria codes
BA1
African/African American FAF >0.1% gnomAD v2.1 non-cancer: African/African American exome Popmax Filtering AF (95% confidence) 2.8% (0.02758; 733/23,606 alleles, 9 homozygotes and gnomAD v4.1 Grpmax AF = 2.898%
BS3
No impact on splicing in laboratory assays using nonsense-mediated decay inhibition (PMID: 27629256).
No aberrant splicing was identified in RT-PCR analysis using nonsense-mediated decay inhibition in variant carrier LCLs. The variant has no impact on splicing in minigene analysis. PubMed:27629256
Not Met criteria codes
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PVS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP7
Intronic variant at -19 in intron 15, not beyond -21
BP4
SpliceAI variant gene Δ type Δ score pre-mRNA position 3-37047500-T-A MLH1 (ENSG00000076242.16 / ENST00000231790.8 / NM_000249.4, NM_001354629.2, NM_001354628.2) Acceptor Loss 0.02 19 bp Donor Loss 0.01 183 bp Acceptor Gain 0.41 59 bp Donor Gain 0.00 MaxEntScan Ref:9.34, Alt: 6.35, Diff:-2.98 NNSplice Splice site predictions for 2 sequences with donor score cutoff 0.00, acceptor score cutoff 0.00 (exon/intron boundary shown in larger font): Donor site predictions for WT : Start End Score Exon Intron Acceptor site predictions for WT : Start End Score Intron Exon 66 106 0.99 catgttcttgcttcttcctaggagccagcaccgctctttga Donor site predictions for MUT : Start End Score Exon Intron Acceptor site predictions for MUT : Start End Score Intron Exon 66 106 0.99 caagttcttgcttcttcctaggagccagcaccgctctttga
BP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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