chr3-37014545-G-A

Position:

chr3-37014545-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The ENST00000231790.8(MLH1):c.790+1G>A variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,208 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

MLH1
ENST00000231790.8 splice_donor

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic reviewed by expert panel P:18

Conservation

PhyloP100: 9.57

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 3-37014545-G-A is Pathogenic according to our data. Variant chr3-37014545-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 90356.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37014545-G-A is described in Lovd as [Pathogenic]. Variant chr3-37014545-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MLH1	NM_000249.4 linkuse as main transcript	c.790+1G>A		splice_donor_variant		ENST00000231790.8	NP_000240.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MLH1	ENST00000231790.8 linkuse as main transcript	c.790+1G>A		splice_donor_variant		1	NM_000249.4	ENSP00000231790	P1	P40692-1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152090

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000214

AC:

AN:

1403754

Hom.:

Cov.:

AF XY:

0.00000142

AC XY:

AN XY:

701832

show subpopulations

Gnomad4 AFR exome

AF:

0.0000310

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000189

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152208

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74422

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:18

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:7

Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 01, 2023	The MLH1 c.790+1G>A variant (also known as IVS9+1G>A) disrupts a canonical splice site and has been shown to cause an in-frame skipping of exons 9-10 (PMID: 16395668 (2006)), at a level greater the alternatively spliced isoforms observed in normal cells (PMIDs: 9490293 (1998), 7728749 (1995)). The frequency of this variant in the general population, 0.0000066 (1/152090 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. The variant has been reported in multiple individuals with colorectal cancer or Lynch syndrome (PMIDs: 26895986 (2016), 25133505 (2014), 25107687 (2014), 24344984 (2013), 20937110 (2010), 20305446 (2010), 17054581 (2006), 16395668 (2006), 15955785 (2005), 15849733 (2005), 11524701 (2001)). A functional study also indicates the variant causes a significant loss of DNA mismatch repair activity (PMID: 11781295 (2002)). Based on the available information, this variant is classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 05, 2023	Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Identified in individuals with MLH1-related cancers with concordant immunohistochemistry in published literature (Cummingham et al., 2001; Ward et al., 2002; Casey et al., 2005; Sanchez de Abajo et al., 2006; Ewald et al., 2007; Sheng et al., 2009; Alvarez et al., 2010; Haraldsdottir et al., 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 15200905, 15849733, 17440950, 16142001, 12200596, 15289847, 18692554, 18726168, 16341804, 18713544, 16276679, 12658575, 25525159, 25107687, 25133505, 25338684, 32549215, 31830689, 32294063, 17054581, 19248199, 16288214, 15955785, 20587412, 20937110, 15872200, 15713769, 9057658, 11524701, 26895986, 28874130, 28248820, 26666765, 20305446, 29887214, 30093976, 34178123, 32490589, 30787465, 16395668) -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Colorectal cancer, hereditary nonpolyposis, type 2

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jul 17, 2023	This variant is considered 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. Functional studies indicate this variant impacts protein function [PMID: 8574961, 11781295]. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 19, 2022	- -

Lynch syndrome

Pathogenic:2

Pathogenic, reviewed by expert panel	research	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	Sep 05, 2013	Variant causes splicing aberration interrupting protein function: full inactivation of variant allele -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 15, 2016	Variant summary: The MLH1 c.790+1G>A variant involves the alteration of a conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict that this variant ablishes the 5' splicing donor site, which was confirmed by an in vitro study (Auclair_2006). This variant has been found in numerous LS patients and is absent in 115338 control chromosomes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 14, 2021	This variant causes a G to A nucleotide substitution at the +1 position of intron 9 splice donor site of the MLH1 gene. Functional RNA studies have shown that this variant causes a skipping of exons 9 and 10 (PMID: 16395668, 20937110) at a level far greater than the low-level alternate splicing reported in normal cells (PMID: 7728749, 9490293). This alternate splicing results in the deletion of amino acids 227-295 and loss of mismatch repair activity of the MLH1 protein (PMID: 11781295). This variant has been reported in individuals affected with Lynch syndrome (PMID: 15955785, 16395668, 19248199, 20937110, 25107687, 26666765, 26895986, 28874130) and colorectal cancer (PMID: 11524701,15713769). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MLH1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 14, 2021	The c.790+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 9 of the MLH1 gene. This mutation has been seen in multiple individuals with personal and family histories of colon cancer (Cunningham JM et al. Am. J. Hum. Genet. 2001 Oct;69:780-90; Rosty C et al. BMJ Open. 2016 Feb;6(2):e010293; Haraldsdottir S et al. Fam. Cancer 2016 Apr;15(2):253-60; Rossi BM et al. BMC Cancer 2017 Sep;17(1):623). In addition, a functional study utilizing RNA from an individual carrying this mutation found that it leads to skipping of coding exons 9 and 10 (Auclair J et al. Hum. Mutat. 2006 Feb;27:145-54; Ambry internal data). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. -

Lynch syndrome 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Department of Molecular Diagnostics, Institute of Oncology Ljubljana

Apr 02, 2020

- -

Lynch-like syndrome

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Constitutional Genetics Lab, Leon Berard Cancer Center

Jul 01, 2019

- -

Colonic neoplasm

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences

Sep 12, 2021

- -

Hereditary nonpolyposis colorectal neoplasms

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 21, 2024

This sequence change affects a donor splice site in intron 9 of the MLH1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with Lynch syndrome and colorectal cancer (PMID: 11524701, 15849733, 15955785, 17054581, 20937110, 24710284). This variant is also known as IVS9+1G>A. ClinVar contains an entry for this variant (Variation ID: 90356). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that disruption of this splice site affects MLH1 function (PMID: 11781295). Studies have shown that disruption of this splice site results in skipping of exons 9-10, but is expected to preserve the integrity of the reading-frame (PMID: 16395668). For these reasons, this variant has been classified as Pathogenic. -

Endometrial carcinoma

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

CZECANCA consortium

Feb 21, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.42

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Pathogenic

1.2

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

0.99

MutationTaster

Benign

1.0

D;D;D;D;D;D

GERP RS

4.9

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.94

SpliceAI score (max)

0.87

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.87

Position offset: -1

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over