chr3-37025629-T-TTTTTTTTTTA
Variant summary
Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate
The NM_000249.4(MLH1):c.1039-8_1039-7insTTTTTTTTTA variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★).
Frequency
Genomes: 𝑓 0.0 ( 0 hom., cov: 19)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
MLH1
NM_000249.4 splice_region, intron
NM_000249.4 splice_region, intron
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.0980
Publications
3 publications found
Genes affected
MLH1 (HGNC:7127): (mutL homolog 1) The protein encoded by this gene can heterodimerize with mismatch repair endonuclease PMS2 to form MutL alpha, part of the DNA mismatch repair system. When MutL alpha is bound by MutS beta and some accessory proteins, the PMS2 subunit of MutL alpha introduces a single-strand break near DNA mismatches, providing an entry point for exonuclease degradation. The encoded protein is also involved in DNA damage signaling and can heterodimerize with DNA mismatch repair protein MLH3 to form MutL gamma, which is involved in meiosis. This gene was identified as a locus frequently mutated in hereditary nonpolyposis colon cancer (HNPCC). [provided by RefSeq, Aug 2017]
MLH1 Gene-Disease associations (from GenCC):
- Lynch syndromeInheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, ClinGen, Orphanet
- Lynch syndrome 2Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp
- Muir-Torre syndromeInheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Ambry Genetics, G2P, Orphanet
- mismatch repair cancer syndrome 1Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen
- Lynch syndrome 1Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
- ovarian cancerInheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
- malignant pancreatic neoplasmInheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
- rhabdomyosarcomaInheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
- prostate cancerInheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
- breast cancerInheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics
- hereditary breast carcinomaInheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
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ACMG classification
Classification was made for transcript
Our verdict: Likely_benign. The variant received -2 ACMG points.
BP6
Variant 3-37025629-T-TTTTTTTTTTA is Benign according to our data. Variant chr3-37025629-T-TTTTTTTTTTA is described in ClinVar as Benign. ClinVar VariationId is 215450.Status of the report is criteria_provided_single_submitter, 1 stars.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_000249.4. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| MLH1 | NM_000249.4 | MANE Select | c.1039-8_1039-7insTTTTTTTTTA | splice_region intron | N/A | NP_000240.1 | |||
| MLH1 | NM_001354628.2 | c.1039-8_1039-7insTTTTTTTTTA | splice_region intron | N/A | NP_001341557.1 | ||||
| MLH1 | NM_001354629.2 | c.940-8_940-7insTTTTTTTTTA | splice_region intron | N/A | NP_001341558.1 |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| MLH1 | ENST00000231790.8 | TSL:1 MANE Select | c.1039-8_1039-7insTTTTTTTTTA | splice_region intron | N/A | ENSP00000231790.3 | |||
| MLH1 | ENST00000456676.7 | TSL:1 | c.1039-8_1039-7insTTTTTTTTTA | splice_region intron | N/A | ENSP00000416687.3 | |||
| MLH1 | ENST00000413740.2 | TSL:1 | c.1039-8_1039-7insTTTTTTTTTA | splice_region intron | N/A | ENSP00000416476.2 |
Frequencies
GnomAD3 genomes 0.00 AC: 0AN: 135300Hom.: 0 Cov.: 19
GnomAD3 genomes
AF:
AC:
0
AN:
135300
Hom.:
Cov.:
19
Gnomad AFR
AF:
Gnomad AMI
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Gnomad AMR
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Gnomad ASJ
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Gnomad SAS
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Gnomad NFE
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Gnomad OTH
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GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0AN: 1103272Hom.: 0 Cov.: 20 AF XY: 0.00 AC XY: 0AN XY: 545244
GnomAD4 exome
Data not reliable, filtered out with message: AC0;AS_VQSR
AF:
AC:
0
AN:
1103272
Hom.:
Cov.:
20
AF XY:
AC XY:
0
AN XY:
545244
African (AFR)
AF:
AC:
0
AN:
21112
American (AMR)
AF:
AC:
0
AN:
17426
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
17588
East Asian (EAS)
AF:
AC:
0
AN:
29082
South Asian (SAS)
AF:
AC:
0
AN:
38370
European-Finnish (FIN)
AF:
AC:
0
AN:
36848
Middle Eastern (MID)
AF:
AC:
0
AN:
3212
European-Non Finnish (NFE)
AF:
AC:
0
AN:
895858
Other (OTH)
AF:
AC:
0
AN:
43776
GnomAD4 genome 0.00 AC: 0AN: 135300Hom.: 0 Cov.: 19 AF XY: 0.00 AC XY: 0AN XY: 65414
GnomAD4 genome
Data not reliable, filtered out with message: AC0
AF:
AC:
0
AN:
135300
Hom.:
Cov.:
19
AF XY:
AC XY:
0
AN XY:
65414
African (AFR)
AF:
AC:
0
AN:
33960
American (AMR)
AF:
AC:
0
AN:
13720
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
3320
East Asian (EAS)
AF:
AC:
0
AN:
4952
South Asian (SAS)
AF:
AC:
0
AN:
4486
European-Finnish (FIN)
AF:
AC:
0
AN:
7974
Middle Eastern (MID)
AF:
AC:
0
AN:
268
European-Non Finnish (NFE)
AF:
AC:
0
AN:
63916
Other (OTH)
AF:
AC:
0
AN:
1812
ClinVar
Significance: Benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Hereditary nonpolyposis colorectal neoplasms Benign:1
Jan 19, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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