Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_000249.4(MLH1):c.42A>C (p.Thr14=)

Curation Version - 1.0
Curation History
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CA010370

135853 (ClinVar)

Gene: MLH1

Condition: Lynch syndrome 1

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 1f40ba2a-2d8a-44e6-b23e-d4c408223d93

Approved on: 2024-09-19

Published on: 2024-10-11

HGVS expressions

NM_000249.4:c.42A>C

NM_000249.4(MLH1):c.42A>C (p.Thr14=)

NC_000003.12:g.36993589A>C

CM000665.2:g.36993589A>C

NC_000003.11:g.37035080A>C

CM000665.1:g.37035080A>C

NC_000003.10:g.37010084A>C

NG_007109.2:g.5240A>C

NG_008418.1:g.4716T>G

ENST00000413740.2:c.42A>C

ENST00000450420.6:c.42A>C

ENST00000456676.7:c.42A>C

ENST00000458009.6:c.42A>C

ENST00000616768.6:c.42A>C

ENST00000673673.2:c.42A>C

ENST00000231790.8:c.42A>C

ENST00000432299.6:c.42A>C

ENST00000442249.6:n.57A>C

ENST00000673713.1:n.73A>C

ENST00000673715.1:c.42A>C

ENST00000673897.1:c.42A>C

ENST00000673899.1:c.42A>C

ENST00000673947.1:c.42A>C

ENST00000673972.1:c.42A>C

ENST00000674111.1:c.42A>C

ENST00000231790.6:c.42A>C

ENST00000432299.5:c.42A>C

ENST00000442249.5:c.42A>C

ENST00000454028.5:c.42A>C

ENST00000456676.6:c.17A>C

ENST00000457004.5:c.42A>C

ENST00000536378.5:c.-591A>C

NM_000249.3:c.42A>C

NM_001258271.1:c.42A>C

NM_001258273.1:c.-591A>C

NM_001167617.2:c.-475A>C

NM_001167618.2:c.-904A>C

NM_001167619.2:c.-817A>C

NM_001258274.2:c.-1054A>C

NM_001354615.1:c.-585A>C

NM_001354616.1:c.-585A>C

NM_001354617.1:c.-677A>C

NM_001354618.1:c.-909A>C

NM_001354619.1:c.-1033A>C

NM_001354620.1:c.-243A>C

NM_001354621.1:c.-1002A>C

NM_001354622.1:c.-1115A>C

NM_001354623.1:c.-1024A>C

NM_001354624.1:c.-785A>C

NM_001354625.1:c.-683A>C

NM_001354626.1:c.-780A>C

NM_001354627.1:c.-1012A>C

NM_001354628.1:c.42A>C

NM_001354629.1:c.42A>C

NM_001354630.1:c.42A>C

NM_001167617.3:c.-475A>C

NM_001167618.3:c.-904A>C

NM_001167619.3:c.-817A>C

NM_001258271.2:c.42A>C

NM_001258273.2:c.-591A>C

NM_001258274.3:c.-1054A>C

NM_001354615.2:c.-585A>C

NM_001354616.2:c.-585A>C

NM_001354617.2:c.-677A>C

NM_001354618.2:c.-909A>C

NM_001354619.2:c.-1033A>C

NM_001354620.2:c.-243A>C

NM_001354621.2:c.-1002A>C

NM_001354622.2:c.-1115A>C

NM_001354623.2:c.-1024A>C

NM_001354624.2:c.-785A>C

NM_001354625.2:c.-683A>C

NM_001354626.2:c.-780A>C

NM_001354627.2:c.-1012A>C

NM_001354628.2:c.42A>C

NM_001354629.2:c.42A>C

NM_001354630.2:c.42A>C

Benign

BS4 BS1 BP4 BP7

BA1 PM6 PM2 PM3 PM1 PM5 PM4 BS2 PVS1 BS3 BP2 BP1 BP3 BP5 PS3 PS2 PS4 PS1 PP4 PP1 PP3 PP2

Evidence Links 0

Expert Panel

InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP

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.42A>C (p.Thr14=) variant is a synonymous (silent) variant in exon 1 of MLH1. The highest population minor allele frequency in gnomAD v2.1 non-cancer cohort is 0.0009 (26/19,252 alleles) in the East Asian population and GnomAD v4.1 Grpmax AF is 0.0002524, which is higher than the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP threshold (0.0001) for BS1, meeting this criterion (BS1). The variant does not segregate with disease (BS4; Australian Colon Cancer Family Registry). The results from 3/3 in silico splice predictors, (SpliceAI, NNSplice, MaxEntScan), predict no splice impact (BP4). The variant is a synonymous variant outside the splice region with no predicted impact on splicing (BP7). In summary, this variant meets the criteria to be classified as benign for Lunch syndrome. ACMG/AMP criteria met, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP: BS1, BS4, BP4, BP7.

BS4

Segregation odds of pathogenicity <0.05 (Australian Colon Cancer Family Registry)

BS1

East Asian filtering AF >0.01%: gnomAD v2.1 non-cancer: exome East Asian Popmax Filtering AF (95% confidence) 0.09% (0.0009346; 26/19,252 alleles). GnomAD v4.1 AF = 0.0002524 > 0.0001

BP4

No predicted impact on splicing (MaxEntScan, SpliceAI, NNSplice) MaxEntScan - No change SpliceAI variant gene Δ type Δ score pre-mRNA position 3-36993589-A-C MLH1 (ENSG00000076242.16 / ENST00000231790.8 / NM_000249.4, NM_001354629.2, NM_001354628.2) Acceptor Loss 0.00 Donor Loss 0.01 250 bp Acceptor Gain 0.00 Donor Gain 0.01 74 bp 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 30 70 0.51 ccaaaatgtcgttcgtggcaggggttattcggcggctggac Donor site predictions for MUT : Start End Score Exon Intron Acceptor site predictions for MUT : Start End Score Intron Exon 30 70 0.51 ccaaaatgtcgttcgtggcaggggttattcggcggctggac

BP7

Synonymous variant beyond +7/–21 (located in exon and closest exon boundary is c.116)

BA1