GeneBe

rs267607788

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 10P and 1B. PM2PP5_Very_StrongBP4

The NM_000249.4(MLH1):​c.791-5T>G variant causes a splice region, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★).

Frequency

Genomes: not found (cov: 32)

Consequence

MLH1
NM_000249.4 splice_region, intron

Scores

2
Splicing: ADA: 0.7810
2

Clinical Significance

Pathogenic reviewed by expert panel P:7

Conservation

PhyloP100: 4.04

Publications

3 publications found
Variant links:
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 syndrome
    Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, ClinGen, Orphanet
  • Lynch syndrome 2
    Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp
  • Muir-Torre syndrome
    Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Ambry Genetics, G2P, Orphanet
  • mismatch repair cancer syndrome 1
    Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen
  • Lynch syndrome 1
    Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
  • ovarian cancer
    Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
  • malignant pancreatic neoplasm
    Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
  • rhabdomyosarcoma
    Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
  • prostate cancer
    Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
  • breast cancer
    Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics
  • hereditary breast carcinoma
    Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 3-37017501-T-G is Pathogenic according to our data. Variant chr3-37017501-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 90374.Status of the report is reviewed_by_expert_panel, 3 stars.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.68). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MLH1NM_000249.4 linkc.791-5T>G splice_region_variant, intron_variant Intron 9 of 18 ENST00000231790.8 NP_000240.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MLH1ENST00000231790.8 linkc.791-5T>G splice_region_variant, intron_variant Intron 9 of 18 1 NM_000249.4 ENSP00000231790.3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.00
Hom.:
0

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:7
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Colorectal cancer, hereditary nonpolyposis, type 2 Pathogenic:2
Jan 01, 2019
Institute of Human Genetics, University of Leipzig Medical Center
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Nov 26, 2021
Human Genetics Bochum, Ruhr University Bochum
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

ACMG criteria used to clasify this variant: PVS1, PM2, PS3 -

Lynch syndrome Pathogenic:2
Jul 02, 2018
Mendelics
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Sep 05, 2013
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)
Significance:Pathogenic
Review Status:reviewed by expert panel
Collection Method:research

Variant causes splicing aberration: full inactivation of variant allele. -

not provided Pathogenic:1
Oct 01, 2022
CeGaT Center for Human Genetics Tuebingen
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

MLH1: PM2, PS3:Moderate, PP4, PS4:Supporting -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
May 26, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant has been observed in individuals with Lynch syndrome (PMID: 16395668, 18561205; Invitae). For these reasons, this variant has been classified as Pathogenic. Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 16395668, 18561205, 26761715). ClinVar contains an entry for this variant (Variation ID: 90374). This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 9 of the MLH1 gene. It does not directly change the encoded amino acid sequence of the MLH1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. -

Hereditary cancer-predisposing syndrome Pathogenic:1
Apr 03, 2019
Color Diagnostics, LLC DBA Color Health
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.68
CADD
Benign
17
DANN
Benign
0.84
PhyloP100
4.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Mutation Taster
=0/100
disease causing (ClinVar)

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.78
dbscSNV1_RF
Benign
0.63
Splicevardb
3.0
SpliceAI score (max)
0.18
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs267607788; hg19: chr3-37058992; API