3-37049020-A-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong

The NM_000249.4(MLH1):​c.2103+3A>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. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Consequence

MLH1
NM_000249.4 splice_region, intron

Scores

2
Splicing: ADA: 0.9981
2

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 5.28
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.
PP5
Variant 3-37049020-A-G is Pathogenic according to our data. Variant chr3-37049020-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 90047.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37049020-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MLH1NM_000249.4 linkc.2103+3A>G splice_region_variant, intron_variant Intron 18 of 18 ENST00000231790.8 NP_000240.1 P40692-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MLH1ENST00000231790.8 linkc.2103+3A>G splice_region_variant, intron_variant Intron 18 of 18 1 NM_000249.4 ENSP00000231790.3 P40692-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
29
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Colorectal cancer, hereditary nonpolyposis, type 2 Pathogenic:2
Feb 09, 2024
Myriad Genetics, Inc.
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 32133419, 31641931, 38311346]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 21642682; Myriad internal data]. -

Jun 08, 2023
Baylor Genetics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Pathogenic:2
Sep 19, 2024
Ambry Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.2103+3A>G intronic pathogenic mutation results from an A to G substitution 3 nucleotides after coding exon 18 in the MLH1 gene. This alteration was identified in individuals with a family history that met Amsterdam I criteria for Lynch syndrome and/or showed loss of MLH1 and PMS2 protein expression by immunohistochemistry in their colorectal tumors (Ambry internal data). This alteration was also identified in a French family suspected of having Lynch syndrome; however, the clinical phenotype and tumor characteristics were not provided (Bonadona, V et al. JAMA. 2011 Jun 8;305(22):2304-10). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may weaken the native splice donor site. RNA studies have demonstrated this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Nov 07, 2022
Color Diagnostics, LLC DBA Color Health
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant causes an A>G nucleotide substitution at the +3 position of intron 18 of the MLH1 RNA. Computational splicing tools predict that this variant may have a significant impact on RNA splicing. The Universal Mutation Database (UMD) reported the skipping of exon 18 as detected in the RT-PCR analysis of carrier RNA (http://www.umd.be/MLH1/4DACTION/Web_D_splice/53). This variant has been reported in a French family suspected of having Lynch syndrome (PMID: 21642682) and in individuals with a family history that met Amsterdam I criteria for Lynch syndrome and/or showed loss of MLH1 and PMS2 protein expression by immunohistochemistry in their colorectal tumors (ClinVar SCV000276974.5, communication with external laboratory). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

not provided Pathogenic:1
Sep 01, 2023
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The MLH1 c.2103+3A>G variant has been reported in the published literature in an individual with Lynch Syndrome (PMID: 21642682 (2011)). This variant was also determined to result in aberrant MLH1 splicing (PMID: 31642931 (2019)). In addition, internal laboratory data indicates that this variant was observed in an individual with colorectal cancer. This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant may affect proper MLH1 mRNA splicing. Based on the available information, this variant is classified as likely pathogenic. -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
Oct 19, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change falls in intron 18 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 likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with Lynch syndrome (external communication, internal data). ClinVar contains an entry for this variant (Variation ID: 90047). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 18, but is expected to preserve the integrity of the reading-frame (internal data). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.33
CADD
Benign
23
DANN
Benign
0.96

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.92
SpliceAI score (max)
0.42
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.42
Position offset: -3

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs587778976; hg19: chr3-37090511; API